Management of Breast Cancer 2nd Edition

i

GUIDELINES DEVELOPMENT AND OBJECTIVES v

GUIDELINES DEVELOPMENT GROUP ix

REVIEW COMMITTEE xi

EXTERNAL REVIEWERS xiii

ALOGRITHM FOR TREATMENT OF OPERABLE INVASIVE CARCINOMA (IDC) xiv

ALOGRITHM FOR TREATMENT OF LOCALLY ADVANCE BREAST CANCER xv

1 INTRODUCTION 1

1.1 Risk factors 2

1.1.1 Gender 2

1.1.2 Age 2

1.1.3 History of Neoplastic Disease of the Breast 2

1.1.4 Family History 3

1.1.5 Radiation Exposure 3

1.1.6 Reproductive Hormone 3

1.1.7 Breast Density 3

1.1.8 Lifestyle 4

2 SCREENING 5

2.1 Screening on General Population 5

2.2 Screening on High Risk Group 7

3 REFERRAL TO SURGICAL/ BREAST CLINIC 9

4 ASSESSMENT/DIAGNOSIS IN SPECIALIST CLINIC 10

4.1 Triple Assessment 10

4.2 Diagnostic Accuracy of Ultrasound and Mammography Together Compared With Ultrasound or Mammography Alone 10

4.3 Preoperative Assessment of the Breast 12

4.3.1 Role Preoperative Magnetic Resonance Imaging of Early and Locally Advanced Breast Cancer 12

5 BASELINE STAGING INVESTIGATION 14

5.1 Early Breast Cancer 14

5.2 Advanced Breast Cancer 15

5.3 Positron Emission tomography (PET) or PET/CT in Staging 16

TABLE OF CONTENTS

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6 LABORATORY DIAGNOSIS 18

6.1 Fine Needle Aspiration Cytology (FNAC) vs Core Biopsy (CB) 18

6.2 Human Epidermal Growth Factor Receptor 2( HER-2) Testing in Breast Cancer 19

6.3 Pathology Reporting for Breast Cancer 20

7 TREATMENT OF BREAST CANCER 21

7.1 Surgical Management for Women with Early Breast Cancer 21

7.2 Contraindications of Breast Conserving Surgery (BCS) 21

7.3 Tumour Free Margin in Breast Conserving Surgery 22

7.4 Axillary Surgery in Early Breast Cancer 23

7.4.1 Indications for Sentinel Lymph Node Biopsy (SLNB) in Breast Cancer 23

7.5 Immediate Breast Reconstruction vs Delayed Breast Reconstruction 24

7.6 Management of Locally Advanced Breast Cancer 26

7.6.1 Neo-adjuvant Chemotherapy in Locally Advanced Breast Cancer 26

7.6.2 Factor Affecting Responds to Neo-adjuvant Chemotherapy 27

7.7 Surgery for the Primary Tumour in Metastatic Breast Cancer 27

7.8. Resection of Metastases in Metastatic Breast Cancer 28

7.9 Systemic Therapy 28

7.9.1 Indications and Benefit of Adjuvant Chemotherapy in Early Breast Cancer 28

7.9.2 Indications and Benefit for Neo-adjuvant Chemotherapy compared to Adjuvant Chemotherapy in Early Breast Cancer 30

7.9.3 Indications and Benefit of Taxane Based Regimens compared to Anthracycline Based Regimens in Early Breast Cancer 31

7.9.4. Indications and Survival Benefit for Anti-Her 2 Adjuvant Treatment in Early or Locally Advanced Breast Cancer 32

7.10 Endocrine Therapy 33

7.10.1 Endocrine Therapy in Early Invasive Breast Cancer and Ductal Carcinoma in Situ (DCIS) 33

7.10.2 Ovarian Suppression or Ovarian Ablation in addition to Standard Adjuvant therapy Consisting of Chemotherapy and Tamoxifen in Premenopausal Breast Cancer Patients 33

7.11 Aromatase Inhibitors 34

7.11.1 The Benefits of Aromatase Inhibitors vs Tamoxifen in the Adjuvant in Post-menopausal Breast Cancer Patients 34

7.11.2. Benefits of Aromatase Inhibitors vs Tamoxifen in the Advanced Setting in Post-Menopausal Breast Cancer Patients 35

7.12 Radiotherapy 35

7.12.1 Post-Mastectomy Radiotherapy in Breast Cancer 35

7.12.2 Radiotherapy Post-Breast Conserving Surgery in Breast Cancer 36

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8 PSYCHOLOGICAL SUPPORT 37

8.1 Assessment of Distress 37

8.2 Cognitive Behaviour Therapy 38

8.3 Psychosocial Support 39

8.4 Breast Care Nurse (BCN) 40

8.5 Psycho-education Programmes 42

8.6 Palliative Care 43

9 FOLLOW UP 45

10 LIFESTYLE MODIFICATION IN BREAST CANCER SURVIVORS 46

11 FAMILIAL BREAST CANCER 47

11.1 Genetic Counselling for Inherited Risk to Hereditary Breast and Ovarian Cancer 47

11.2 Interventions which Reduce the Incidence and Mortality of Breast and Ovarian Cancer in Women Identified as High Risk by Personal or Family History Positive Genetic Test Results or Both 49

11.3. Intensive Screening 49

11.3.1 Breast Cancer 49

11.3.2 Ovarian Cancer 49

11.4. Preventive Strategies 50

11.4.1 Tamoxifen Raloxifene and Anastrazole 50

11.4.2 Oral Contraceptives 50

11.4.3 Prophylactic Surgery 50

11.4.4 Bilateral Prophylactic Mastectomy 50

11.4.5 Contralateral Prophylactic Mastectomy 51

11.4.6 Bilateral Salpingo-oophorectomy 51

References 53

Appendix 1: Search Terms 62

Appendix 2 : Clinical Questions 64

Appendix 3 : AJCC Staging (TNM Classification) 7th Edition 67

Appendix 4 : Minimum Dataset for the Histopathology Reporting of Breast Cancer 72

List of Abbreviation 74

Acknowledgement 76

Disclosure Statement 76

Source of Funding 76

LEVELS OF EVIDENCE SCALE AND GRADES OF RECOMMENDATION

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v

GUIDELINES DEVELOPMENT AND OBJECTIVES

GUIDELINES DEVELOPMENT

The development group for this Clinical Practice Guidelines (CPG) consisted of breast

and endocrine surgeons, oncologists, radiologists, pathologists, palliative physicians,

geneticists, family medicine specialists, a clinical psychologist, public health physicians,

a nursing lecturer, a nurse manager and a member of breast cancer group support. They

were from the Ministry of Health (MOH), Ministry of Higher Education, private healthcare

institution and non-governmental organisations. There was an active involvement of the

review committee during the process of development of these guidelines.

Literature search was carried out at the following electronic databases: PUBMED/

MEDLINE, Cochrane Database of Systemic Reviews (CDSR), International Health

Technology Assessment websites, Journal full text via OVID search engine, guidelines

databases. (Refer Appendix 1 for Search Terms) In addition, the reference lists of all

retrieved articles were searched to identify relevant studies. Experts in the field were

also contacted to obtain further studies. All searches were conducted between 24 March

2009 through 20 February 2010.

Reference was also made to other guidelines on management of breast cancer such as

National Institute for Clinical Excellence (NICE) 2009 Breast Cancer Screening - Early

and Locally Advanced Breast Cancer: Diagnosis and Treatment, NICE 2009 Advanced

Breast Cancer: Diagnosis and Treatment, New Zealand Guidelines Group (NZGG) 2009

Management of Early Breast Cancer, Scottish Intercollegiate Guidelines Network (SIGN)

2005 Management of Breast Cancer in Women, Federaal Kenniscentrum voor de

Gezondheidszorg (KCE) 2006 Breast Cancer Screening, National Comprehensive Cancer

Network (NCCN) Clinical Practice Guidelines in Oncology 2008 Breast Cancer, National

Health and Medical Research Council (NHMRC) 2001 CPG for the Management of Early

Breast Cancer. These CPGs were evaluated using the Appraisal of Guidelines for Research

and Evaluation (AGREE) prior to them being use as references.

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The clinical questions were developed under ten major subtopics and members of

the development group were assigned individual questions within these subtopics.

(Refer Appendix 2 for Clinical Questions) The group members met a total of 35 times

throughout the development of these guidelines. All literatures retrieved were appraised

by at least two members and presented in the form of evidence tables and discussed

during development group meetings. Later, all statements and recommendations

formulated were agreed upon by both the development group and review committee.

Where evidence was insufficient, the recommendations were derived by consensus of the

development group and review committee. These CPG are based largely on the findings

of systematic reviews, meta-analyses and clinical trials retrieved with local practices

taken into consideration.

The articles were graded using the US/Canadian Preventive Services Task Force Level of

Evidence (2001), while the grading of recommendation in these guidelines was modified

from Grades of Recommendation of the Scottish Intercollegiate Guidelines Network (SIGN).

The draft guidelines were externally reviewed and posted on the MOH Malaysia website

for comment and feedback. These guidelines had also been presented to the Technical

Advisory Committee for CPG and the Health Technology Assessment (HTA) and CPG

Council MOH Malaysia for review and approval.

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OBJECTIVETo provide evidence-based recommendations for the optimal care of women with breast cancer and women at risk of breast cancer

CLINICAL QUESTIONSRefer Appendix 2

TARGET POPULATION

Inclusion criteria• Women with early, advanced and metastatic breast cancer and women at

risk of breast cancer

Exclusion criteria• Nonepithelialbreastmalignancy

• Specificgroupswithbreastcancer–breastcancerinelderly,breastcancerin pregnancy, pregnancy after breast cancer, hormone replacement therapy after breast cancer and male breast cancer

TARGET GROUP/USER

These guidelines are applicable to all healthcare professionals who are involved in the management of patients with breast cancer:-

• GeneralPractitioner/FamilyMedicineSpecialist• BreastCareNurse/OncologyNurse/PalliativeNurse/CommunityNurse• GeneralSurgeon• BreastandEndocrineSurgeon• Radiologist• Radiotherapist/Oncologist• Pathologist/Histopathologist• PalliativeCarePhysician• Geneticist• Psychiatrist/Psychologist/Psycho-oncologist• Counsellor• Pharmacist• Physiotherapist/OccupationalTherapist• Dietician• BreastCancerSupportGroup

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Eligible breast cancer patients post-surgery commencing

chemotherapy within two months

All breast cancer patients post-surgery requiring chemotherapy

HEALTHCARE SETTINGS

Outpatient, inpatient and community settings

PROPOSED CLINICAL AUDIT INDICATORS FOR QUALITY MANAGEMENT

All patients with local recurrence of breast cancer within two years

All patients with surgery for breast cancer

Eligible breast cancer patients post-surgery commencing

chemotherapy within two months

All breast cancer patients post-surgery requiring chemotherapy

Newly diagnosed breast cancer patients receiving initial treatment within two months of presentation

X 100%All compliant newly diagnosed b r e a s t c ance r p a t i e n t s

Percentage of eligible breast cancer patients post-surgery commencing chemotherapy within two months

=

=

= Percentage of local recurrence of breast cancer within two years

X 100%

X 100%

Percentage of newly diagnosed breast cancer patients receiving initial treatment within two monthsof presentation

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GUIDELINES DEVELOPMENT GROUP

Chairperson

Prof. Dr. Yip Cheng HarConsultant Surgeon & LecturerDepartment of SurgeryUniversity Malaya Medical Centre Kuala Lumpur

Members (alphabetical order)

Dr. Anita BaghawiBreast & Endocrine SurgeonDepartment of SurgeryHospital Putrajaya Putrajaya

Dr. Normayah KitanBreast & Endocrine SurgeonDepartment of SurgeryHospital Putrajaya Putrajaya

Dr. Daniel Wong Wai YanConsultant Clinical Oncologist Pantai Cancer CentrePantai Hospital Ayer KerohMelaka

Ms. Ranjit KaurChief Executive OfficerBreast Cancer Welfare Association (BCWA)Selangor

Dr. Hariyati Shahrima Abdul MajidConsultant Health Psychologist & Assistant ProfessorInternational Islamic University of Malaysia (IIUM)Kuala Lumpur

A/P Raja Lexshimi Raja GopalSenior Nursing Lecturer (Oncology)Universiti Kebangsaan Malaysia Medical CentreKuala Lumpur

Dr. Hussain MohamadConsultant Breast & Endocrine SurgeonDepartment of SurgeryHospital Sultanah Nur Zahirah Terengganu

Dr. Sarimah OmarConsultant RadiologistDepartment of RadiologyHospital Melaka Melaka

Dr. Irmi Zarina IsmailFamily Medicine Specialist & LecturerMedicine & Health FacultyUniversiti Putra Malaysia Selangor

Dr. Sheamini SivasampuHead of Healthcare Statistic UnitClinical Research CentreHospital Kuala Lumpur Kuala Lumpur

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A/P. Dr. Kartini RahmatConsultant Radiologist & LecturerDepartment of RadiologyUniversity Malaya Medical Center Kuala Lumpur

Ms. Sin Lian ThyeSenior Nurse ManagerHealth Technology Assessment SectionMedical Development Division MOH Putrajaya

Dr. Keng Wee TeikConsultant Clinical GeneticistGenetic DepartmentHospital Kuala LumpurKuala Lumpur

Dr. Suzaini Mat DaudFamily Medicine SpecialistHealth Clinic ArauPerlis

A/P. Dr. Krishnan Rangaswamy IyengarConsultant Pathologist & LecturerDepartment of PathologyUniversity Malaya Medical Center Kuala Lumpur

Dr. Tan Seng BengSenior Lecturer in Palliative MedicinePalliative Care UnitUniversity Malaya Medical Center Kuala Lumpur

Dr. Loh Ee ChinSenior Lecturer in Palliative MedicinePalliative Care UnitUniversity Malaya Medical Center Kuala Lumpur

Adjunct Professor Dr. Teo Soo HwangChief Executive Cancer Research Initiative Foundation (CARIF)Selangor

Dr. Muhammad Azrif Ahmad AnuarConsultant Clinical Oncologist & LecturerDepartment of Radiotherapy & OncologyUniversiti Kebangsaan Malaysia Medical CenterKuala Lumpur

Prof. Dr. Thong Meow KeongConsultant Clinical Geneticist & Lecturer University Malaya Medical Center Kuala Lumpur

Dr. Mohamad Rafie Md KaslanConsultant PathologistDepartment of PathologyHospital PutrajayaPutrajaya

Dr. Yun Sii IngSenior Consultant Radiologist & Head of DepartmentDepartment of RadiologyHospital Sungai BulohSelangor

Dr. Nor Saleha Ibrahim TaminPublic Health Physician Cancer Unit Non-Communicable Disease SectionDisease Control Division MOHPutrajaya

Dr. Vincent Phua Chee EeClinical OncologistDepartment of OncologyHospital Pulau PinangPulau Pinang

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REVIEW COMMITTEE (alphabetical order)

The draft guidelines were reviewed by a panel of independent expert referees both public and private sectors including non-government organisation and patient advocate, who were asked to comment primarily on the comprehensiveness and accuracy in the interpretation of evidence supporting the recommendations in the guidelines.

Chairperson

Datuk Dr. Noor Hisham AbdullahDeputy Director General of Health (Medical)Ministry of Health MalaysiaPutrajaya

Members (alphabetical order)

Dr. Ednin Hamzah Chief Executive Officer Hospice MalaysiaKuala Lumpur

Dr. Nor Aina EmranConsultant Breast & Endocrine Surgeon Department of SurgeryHospital Kuala Lumpur Kuala Lumpur

Dr. Evelyn Ho Lai MingConsultant RadiologistSime Darby Specialist Centre Megah Selangor

Dr. Patricia Alison GomezConsultant Breast SurgeonPantai HospitalKuala Lumpur

Prof Madya (K) Dato’ Dr Fuad IsmailSenior Consultant Clinical OncologistDepartment of Radiotherapy & OncologyUniversiti Kebangsaan Malaysia Medical CenterKuala Lumpur

Dr. Richard Lim Boon LeongConsultant Palliative Medicine PhysicianHospital SelayangSelangor

Dr. Gerard Lim Chin ChyeHead of DepartmentDepartment of Radiotherapy & OncologyHospital Kuala LumpurKuala Lumpur

Datin Dr. Rugayah BakriDeputy DirectorHealth Technology Assessment SectionMedical Development Division Ministry of Health Malaysia Putrajaya

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Dato’ Prof. Dr. Humairah Samad-CheungSenior Radiologist & Lecturer Director, IIUM Breast CentreInternational Islamic University Malaysia Pahang

Prof. Dr. Sharifah Nor AkmalSenior Consultant PathologistDepartment of PathologyUniversiti Kebangsaan Malaysia Medical CenterKuala Lumpur

Dr. Lim Lay HooiSenior Consultant Plastic Surgery &Reconstruction & Head of Department Department of Plastic Surgery & ReconstructionHospital Pulau Pinang Pulau Pinang

Dr. Siti Fatimah Datuk Dr. Hj. AbbasSenior Consultant RadiologistDepartment of RadiologyHospital MelakaMelaka

Prof. Dr. Looi Lai MengSenior Consultant PathologistDepartment of PathologyUniversity Malaya Medical CenterKuala Lumpur

Dato’ Dr. Suarn SinghSenior Consultant Psychiatric & Hospital DirectorHospital BahagiaPerak

Dr. Mymoon AliasDeputy DirectorFamily Health Development DivisionMinistry of Health Malaysia Putrajaya

Pn. Dasimah AhmadAssistance Director of NursingNursing DivisionMinistry of Health Malaysia Putrajaya

Dato’ Dr. Mohamed Ibrahim WahidPresidentMalaysian Oncology SocietyWijaya International Medical CentreSelangor

Datin Dr. Zaharah MusaSenior Consultant Radiologist & Head of DepartmentDepartment of RadiologyHospital SelayangSelangor

Dato’ Dr. Norain KarimSenior Consultant Pathologist & Head of DepartmentDepartment of PathologyHospital Raja Perempuan Bainun Perak

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EXTERNAL REVIEWERS (alphabetical order)

The following external reviewers provided feedbacks on the draft

Assoc. Prof. Dr. Elizabeth J Wylie (Clinical)Head of Department Diagnostic & Interventional RadiologyRoyal Perth Hospital Australia

Dr. Hayati RadziMaternal Child Health OfficerKedah State Health OfficeKedah

Dr. Jim KolliasConsultant Breast SurgeonRoyal Adelaide HospitalAustralia

Dr. Mary PorteousClinical GeneticsSouth East Scotland Genetic ServiceWestern General Hospital EdinburghUnited Kingdom

Clinical Associate Prof. Michael BilousDirectorPathology, Western Clinical SchoolInstitute of Clinical Pathology and Medical Research(ICPMR) Australia

Prof. Robert GrieveConsultant Clinical OncologistUniversity Hospitals Coventry & Warwickshire CoventryUnited Kingdom

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ALGORITHM FOR TREATMENT OF OPERABLE BREAST CANCER

ALGORITHM FOR TREATMENT OF OPERABLE BREAST CANCER

OPERABLE BREAST CANCER

Surgery

Breast Conserving Surgery1, axillary surgery Mastectomy Axillary surgery ± Reconstruction

Low risk1 Intermediate/high risk2

Intermediate/high risk2 Low risk

Adjuvant radiotherapy + Hormone therapy

Chemotherapy ± Herceptin Hormone therapy

Chemotherapy ± Herceptin

Adjuvant radiotherapy ± Hormone therapy

Adjuvant radiotherapy3

± Hormone therapy

1If the surgical margin is 2 mm, several factors should be cons idered in determining whether re-excision is required. These includes:

• Age

• Tumour histology (lymphovascular invasion, grade, extensive in-situ component and tumour type such as lobular carcinoma)

• Which margin is approximated by tumour (smaller margins may be acceptable for deep and superficial margins)

• Extent of cancer approaching the margin

pN0 and all of the following criteria:

• size of tumour max 2 cm

• Grade 1

• no lymphovascular invasion

• ER-/PR-positive

• HER2- negative

• age > 35 years old

pN0 and at least 1 further criteria:

• size of tumour > 2 cm

• Grade 2/3

• vessel invasion present

• HER2 over-expression

• age < 35 years old

• or pN+(N1-3) and HER2-negative

• pN+(N1-3) and HER2 over-expression

or

• pN+ (N > 4)

2Risk Stratification

Low risk Intermediate risk High risk

3 Indication for adjuvant radiotherapy

• 4 or more lymph nodes

• Positive margin

• ± 1-3 lymph nodes

• ± Node negative disease with high risk of recurrence with 2 or more risk factors such as

- presence of lymphovascular invasion, tumours greater than 2 cm, grade 3 tumours, close resection margin (< 2 mm) and premenopausal status

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ALOGRITHM FOR TREATMENT OF LOCALLY ADVANCED BREAST CANCER

xvi

1

1. INTRODUCTION

The National Cancer Registry (NCR) 2006 reported that there were 3,525 female breast cancer cases in Malaysia and this made it the most commonly diagnosed cancer in women (29.9 % of all new cancers). Breast cancer was the commonest cancer in all ethnic groups and in all age groups in females from the age of 15 years onwards. The overall Age-Standardised Incidence Rate (ASR) was 39.3 per 100,000 population.1, level III

The incidence of breast cancer increased steadily starting from age of 30 years with a peak age specific incidence rate in the 50 - 59 age groups. The situation is similar amongst the Malays, Chinese, and Indians. The incidence rate then declined in the older age groups. Of the cases diagnosed in 2003, 33.6% (one-third) were in women between 40 and 49 years of age. The Chinese women had the highest incidence with an ASR of 46.4 per 100,000 population followed by Indian women with an ASR of 38.1 per 100,000 population and Malay women with an ASR of 30.0 per 100,000 population. Compared to the 2003 - 2005, the ASR is lower for all races, but the age-specific incidence patterns are very similar (Refer to Table 1, Table 2 and Figure 1).1, level III

Table 1: Female Breast Age-Specific Cancer Incidence per 100,000 Population, by Ethnicity and Sex, Peninsular Malaysia 2006

Age groups (year)

0 - 9 10 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70+ CumR

Female Malay 0 0.2 3.2 27 73.8 114.7 78.9 43.4 3.2

Chinese 0 0 4.9 26.9 96.6 176.7 143.3 118.8 5

Indian 0 0 3.2 16.7 82.3 111.1 138.3 140.5 4.3

Table 2: Female Breast Cancer Incidence per 100,000 Population (CR) and Age-Standardised Incidence (ASR), by Ethnicity and Sex, Peninsular Malaysia 2006

Ethnic groupFemale

No % CR ASR

Malay 1,539 47.6 25.3 30.4

Chinese 1,375 42.5 53.2 46.4

Indian 320 9.9 34.9 38.1

2

Figure 1: Female Breast Age-Specific Cancer Incidence per 100,000 Population by Sex, Peninsular Malaysia 2006

1.1 Risk FactorsThere are a number and variety of risk factors that cause the complex multifaceted nature of breast cancer. The risk factors are summarised in Table 3.

1.1.1 GenderFemale has higher risk to develop breast cancer than their male counterparts. The rate for male to develop breast cancer was 1.15 per 100,000 men years compared to female at 42.6 per 100,000 women years.2, level III

1.1.2 AgeThe risk increases from the age of 40 years old for pre-menopausal group and 50 years old for the post menopausal group.3, level II-2; 4, level II-2; 5, level II-2

1.1.3 History of Neoplastic Disease of the Breast

• Prior history of breast cancer carries an elevated risk of developing new primary breast cancer. 6, level III; 7, level II-2

• Person with breast carcinoma in situ (lobular carcinoma in situ and ductal carcinoma in situ) are at high risk to develop invasive breast carcinoma.8, level II-2;

9, level III; 10, level III

• Person with breast tissue biopsy showing proliferative disease with and without atypical cells has an increased risk to develop future breast cancer. Benign breast disease with atypical hyperplasia lesion carries the highest risk to develop breast cancer.3, level II-2; 4, level II-2; 5, level II-2

3

1.1.4 Family HistoryFamily history of breast cancer is an independent risk factor. The risk is higher in women with breast cancer among young first degree relatives. Sister carries more risk than mother.9, level III; 11, level II-2; 12, level II-3; 13, level II-3; 14, level II-2

Carriers of BRCA1 and BRCA2 genetic mutation are at high risk to develop future breast cancer. (Refer to Section 11.2 on Familial Breast Cancer)

1.1.5 Radiation Exposure• Multiple exposures of therapeutic radiation to the chest for cancer at an early

age (less than 20 years old) pose a high risk of developing breast cancer.

• Contralateral breast cancer has been shown to develop after exposures of high dose radiation used during radiotherapy for breast cancer.

• Patients with Hodgkin’s disease receiving radiotherapy at high doses are at high risk to develop breast cancer.

• Screening using mammography has not been shown to significantly affect the breast cancer status.15, level III; 16, level II-2; 17, level II-3; 18, level II-3

1.1.6 Reproductive Factors• First full-term pregnancy more than 30 years old.19, level II-2; 20, level II-2

• Nulliparity.9, level III; 21, level II-2; 22, level II-2; 20, level II-2

• Breastfeeding for duration more than 12 months is protective of breast cancer.23, level III; 24, level II-3; 9, level III; 21, level II-2

• Oral contraceptive use poses a mild increase of breast cancer risk especially if it is use before the first full term pregnancy. However, the risk is lower with low dose preparation. 25, level II-2; 26, level II-2

• Unopposed estrogen use in hysterectomised women mildly increases the risk of breast cancer and only after longer term use ( > 15 years).27, level I; 28, level II-2

• Combination hormone replacement therapy has a mild risk for breast cancer.29, level I

• Age at menopause of more than 55 years old.20, level II-2

• Age at menarche less than 12 years old.19, level II-2; 22, level II-2

1.1.7 Breast DensityHigher breast density from mammography. The risk ranges from two times in scattered fibroglandular density to four times in an extremely dense breast.30, level II-2; 5, level II-2

4

1.1.8 Lifestyle• A body mass index of more than 25 has an increased risk to develop breast

cancer with higher death rate. Small waist and waist-hip ratio (WHR) give a significant protection against breast cancer in pre-menopausal women.31, level II-2;

32, level II-1; 33, level II-2

• Alcohol (especially beer) consumed more than 10 g/day especially among post-menopausal women is a risk factor for developing invasive breast cancer.34, level

1I-2; 35, level II-2; 36, level II-2 • Moderate to vigorous exercise of more than seven hours in a week of physical

activity was inversely related to breast cancer.37, level II-3; 38, level II-2; 39, level II-3

Table 3: Stratifications of Risk FactorsLow Risk (RR 1.0 - 1.4) Moderate Risk (RR 1.5 - 2.0) High Risk (RR > 2.0)

• Alcoholconsumption • Increasingagefrom40yearsold• Personalhistoryofinvasive

breast cancer

• Reproductivefactors:o Increasing age at first full

term pregnancy > 30 yearo Hormone replacement

therapyo Oral contraceptive pill

usage

• Reproductivefactors:o Early menarche

( < 12 year old) (RR 1.02)o Late menopause

( > 55 year old) (OR 2.4)o Nulliparity

• LobularCarcinomaInSitu(LCIS) and Ductal Carcinoma In Situ (DCIS)

• Obesity• Benignbreastdiseasewith

proliferation without atypia• Benignbreastdiseasewith

atypical hyperplasia

• Densebreast• Ionisingradiationfrom

treatment of breast cancer, Hodgkin’s disease, etc.

• CarrierofBRCA1and2genetic mutation

• Significantfamilyhistoryi.e.first degree family with breast cancer

Adapted from:

• WeirR,DayPandAliW.Riskfactorsforbreastcancerinwomen.AsystematicreviewNZHTAREPORTJune2007;10(2);level I

• CancerGeneticServicesInScotland–ManagementofWomenwithaFamilyHistoryofBreast(internetcommunication,13 jan 2010 at Cancer, www.sehd.scot.nhs.uk/mels/HDL2007_08.pdf level III

• Singletary,SE.Ratingtheriskfactorsforbreastcancer.AnnSurgery2003;237(4):474-482.levelII-2

• PharoahPD,DayNE,DuffSetal.Familyhistoryandtheriskofbreastcancer:asystematicreviewand.metaanalysis.Int J Cancer. 1997; 71:800-9

• ColditzGA,WhilletWC,HunterDJ,etal.Familyhistory,age,andriskofbreastcancer.ProspectivedatafromtheNurses’sHealth Study. JAMA. 1993; 270:338-43

• Slattery ML, Kerber RA.A comprehensive evaluation of family history and breast cancer risk,The Utah PopulationDatabase. JAMA; 19993; 270:1563-8

5

2. SCREENING

2.1 Screening on General Population

Benefit of breast self-examination (BSE) appears to be ineffective in reducing breast cancer mortality.40; 41

The effectiveness of CBE is equivocal.42 The current evidence is insufficient to assess the additional benefits and harms of clinical breast examination (CBE).43

The Cochrane Systemic Review (SR) of eight Randomised Clinical Trials (RCTs)

(n=600,000), comparing the effects of mammography screening, found that three

trials with adequate randomisation did not show a significant reduction in breast cancer

mortality at 13 years follow up (RR=0.90, 95% CI 0.79 to 1.02); while four trials with

suboptimal randomisation showed a significant reduction in breast cancer mortality

(RR=0.75, 95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81, 95% CI

0.74 to 0.87. The trials with adequate randomisation did not find an effect of screening

on cancer mortality, including breast cancer, after 10 years follow up (RR=1.02, 95% CI

0.95 to 1.10) or on all-cause mortality after 13 years follow up (RR=0.99, 95% CI 0.95

to 1.03). The SR concluded that screening is likely to reduce breast cancer mortality. As

the effect was lowest in the adequately randomised trials, a reasonable estimate is a 15%

reduction corresponding to an absolute risk reduction of 0.05%. Screening led to 30%

over-diagnosis and overtreatment, or an absolute risk increase of 0.5%. It is not clear

whether screening does more good than harm.44, level I

The results of the Ontario Health Technology Assessment assessing five health technology

assessments, two Preventive Services Task Force reports, one Cochrane SR and eight

RCTs showed that screening mammography in women aged 40 to 49 years at average

risk for breast cancer is not effective in reducing mortality.45, level I

Results of evaluation on the role of various imaging modalities used in the screening and

diagnosis of breast cancer revealed that mammography is the only imaging technique

that has a significant impact on screening of asymptomatic individuals for breast cancer.

Breast ultrasound and breast magnetic resonance imaging (MRI) are frequently used

adjuncts to mammography in treatment planning and staging and not for screening.46, level III

6

Another Cochrane SR of two large population based studies from Russia and Shanghai

(n=388,535) on screening for breast cancer by regular self-examination (self-breast

examination/SBE) or clinical breast examination (CBE) found that there was no statistically

significant difference in breast cancer mortality between the groups (RR=1.05, 95% CI

0.90 to 1.24). In Russia, more cancers were found in the breast self-examination group

than in the control group (RR 1.24, 95% CI 1.09 to 1.41) while this was not the case in

Shanghai (RR 0.97, 95% CI 0.88 to 1.06). Almost twice as many biopsies (n=3,406) with

benign results were performed in the screening groups compared to the control groups

n=1,856, RR=1.88, 95% CI 1.77 to 1.99. The review alsoss concluded that these two

large trials did not suggest a beneficial effect of screening by BSE but suggested increase

in harms in terms of increased numbers of benign lesions identified and biopsied. The

review concluded that screening by BSE or physical examination cannot be recommended.

However, women who continue with BSE or wish to be taught the technique should be

informed on lack of supporting evidence from the two major studies for them to make

informed decision.40, level I

Elmore et al. reviewed breast cancer screening in the community and new screening

modalities. The results from this SR demonstrated significant reductions of 20% to

35% in mortality from breast cancer for women aged 50 to 69 years and slightly less

in women aged 40 to 49 years at 14 years of follow up. Results from seven population-

based community screening programmes in the United States on 463,372 screening

mammography revealed an overall sensitivity of 75.0% and specificity of 92.3%. Review

on CBE screening revealed an overall estimate for sensitivity of 54% (95% CI 48 to

60) and specificity of 94% (95% CI 90 to 97). MRI had not been studied in the general

opulation as a screening tool. This study concluded that in the community, mammography

remains the main screening tool and CBE and BSE are less effective.41, level I

Thistlethwaite et al. examined the evidence for screening CBE and found that it had a low

sensitivity (54%) but high specificity (94%).The highest sensitivity of CBE appeared to be

in women aged 50 - 59 years old while it is lowest in women aged 40 - 49 years old.

Training of clinicians may account for a 27 - 29% difference in sensitivity and 14 - 33%

difference in specificity. However, a negative examination does not exclude the presence

of breast cancer. The effect of CBE on mortality from breast cancer is still unclear.42, level III

7

A recent SR by US Preventive Task Force (USPTF) 2009 recommended biennial screening mammography for women aged 50 to 74 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms. The evidence was insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. The USPTF suggests against teaching BSE and the current evidence is insufficient to assess the additional benefits and harms of CBE beyond screening mammography in women 40 years or older. The evidence was also insufficient to assess the additional benefits and harms of either digital mammography or MRI instead of film mammography as screening modalities for breast cancer.43, level I

Although there is no evidence on the effectiveness of breast self-examination (BSE), the practice of BSE has been seen to empower women and encourage them to take responsibility for their own health. Therefore, BSE is recommended for raising awareness among women at risk rather than as a screening method.47

RECOMMENDATION

Mammographymaybeperformedbiennially inwomenfrom50–74yearsofage.(Grade A)

Breast cancer screening using mammography in low and intermediate risk women aged40–49yearsoldshouldnotbeofferedroutinely.(Grade A)

Womenaged40–49yearsshouldnotbedeniedmammographyscreeningiftheydesire to do so. (Grade C)

BSE is recommended for raising awareness among women at risk rather than as a screening method. (Grade C)

2.2 Screening on High Risk Group

A review by Nelia Alfonso on 49 published papers from 1989 - 2007 concluded that among screening strategies for high-risk women, MRI screening in addition of mammography should be recommended for women who meet at least one of the listed criteria under high risk group in Table 3. It should begin annually at the age of 30 years old and continue for as long as the woman is in good health, as suggested by most guidelines such as National Comprehensive Cancer Network (NCCN), American Cancer Society (ACS) and US Preventive Task Force (USPTF).48, level II-2

8

Based on a SR of 11 nonrandomised studies on the sensitivity, specificity, likelihood ratios

and post-test probability associated with adding MRI to annual mammography screening

of women at very high risk for breast cancer, Ellen et al. concluded that screening women

at very high risk for breast cancer with both MRI and mammography might rule out

cancerous lesions better than mammography alone. The summary negative likelihood

ratio and the probability of a BI-RADS-suspicious lesion (given negative test findings and

assuming a 2% pretest probability of disease) were 0.70 (95% CI 0.59 to 0.82) and 1.4%

(95% CI 1.2% to 1.6%) for mammography alone and 0.14 (95% CI 0.05 to 0.42) and

0.3% (95% CI 0.1% to 0.8%) for the combination of MRI plus mammography, using a

BI-RADS score of 4 or higher as the definition of positive.49, level II-1

While lifetime risk of breast cancer for women diagnosed with LCIS may exceed 20%,

the risk of invasive breast cancer is continuous and only moderate in risk in the 12 years

following local excision. Only one MRI screening study included a selected group of women

with LCIS which showed a small benefit over mammography alone in detecting cancer.

This benefit was not seen in patients with atypical hyperplasia.50, level II-3 The results of MRI

screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia, as

reviewed by Port et al., showed that those who had MRIs were younger (p < 0.001) with

stronger family history of breast cancer (p = 0.02). In MRI-screened patients, 55 biopsies

were recommended in 46/182 (25%) patients in which 46/55 (84%) biopsies were based

on MRI findings alone. The yield of MRI screening overall was cancer detection in 6/46

(13%) of biopsies, 5/182 (3%) of MRI screened patients and 5/478 (1%) of total MRIs.

Therefore, MRI screening generated more biopsies for a large proportion of patients,

and facilitated detection of cancer in only a small highly selected group of patients with LCIS.51, level III

RECOMMENDATION

Screening women at high risk for breast cancer should be done from the age of 30

years with both MRI and mammography as it is more effective than mammography

alone. (Grade B)

MRI screening should not be performed in patients with lobular carcinoma in situ and

atypical hyperplasia. (Grade B)

9

3. REFERRAL TO SURGICAL/BREAST CLINIC

Only two retrospective studies addressed issue on referral to surgical/breast clinic. The

first study provided evidence on the success of categorising patients into urgent and non-

urgent cases. It was noted that 46.7% (n=6,678) of the referrals originated from fast-

track referrals and the remainder 53.3% (n=7,625) came via routine referrals. 71.7% of

the referrals met the referral criteria. Out of the appropriate referrals, 14.4% were cancers

compared to only 0.55% of the inappropriate referrals (p < 0.001). 91.8% of the total

breast cancer patients came from fast-track clinics while 8.2% from routine referrals.

Apart from that, 16.4% of the patients seen in the fast-track clinic were detected with

breast cancer compared to only 1.3% from routine referrals (p < 0.001).52, level III

In another retrospective study, 21 (19.4%) cancers were diagnosed from 108 urgent

referrals. Out of these, 92 patients were given an urgent appointment because of the

presence of high-risk criteria in which 21 (22.8%) cancers were detected. Out of 162

given routine appointments, only two were diagnosed with cancer. In addition to the

assessment by referring physicians, certain high-risk criteria are helpful to select patients

who should be seen urgently. The mean waiting time was 19 days and 154 days for

urgent referral and routine appointments respectively.53, level III

Criteria for early referral 53, level III

• Age > 40 years old women presenting with a breast lump

• Lump > 3 cm in diameter at any age

• Clinical signs of malignancy

10

4. ASSESSMENT/DIAGNOSIS IN SPECIALIST CLINIC

4.1 Triple Assessment

Triple assessment which consists of clinical assessment, imaging (ultrasound and/or mammography) and pathology (cytology and/or histology) is an established method for the diagnosis of breast cancer in many parts of the world.54; 55

The Belgian guidelines recommend that all patients presenting with breast symptom should have a full clinical examination and where a localised abnormality is present, patients should have mammography and/or ultrasonography followed by core biopsy and/or fine needle aspirate cytology depending on the clinician’s, radiologist’s and pathologist’s experience. They also state that if a lesion is considered malignant following clinical examination, imaging or cytology alone, where possible should have histopathological confirmation of malignancy before any definitive surgical procedure. Young women ( < 40 year old) presenting with breast symptoms which are strongly suspicious of breast cancer should be evaluated by means of the triple test approach to exclude or establish a diagnosis of breast cancer.55

The NICE guidelines states that in most cases whether symptomatic or screen detected, the diagnosis of breast cancer is made by triple assessment (clinical examination, mammography and/or ultrasonography imaging with core biopsy and/or fine needle aspiration cytology.54

In a more recent cross sectional study (n=50) on accuracy of triple test score (physical examination, mammography and fine needle aspirate cytology) in the diagnosis of palpable breast lump on women above 35 years old, the accuracy of triple test score was 98%, sensitivity 100%, specificity 95.2%, positive predictive value (PPV) 96.7% and a false positive rate of 3.3%.56, level III

4.2 Diagnostic Accuracy of Ultrasound and Mammography Together Compared With Ultrasound or Mammography Alone

Studies have shown that adjunct ultrasound to mammography improves the diagnostic yield of breast cancer. Corsetti et al. evaluated the contribution of ultrasound in detecting breast cancer in women with dense breasts and negative mammography among 25,572 self referred women. The study found that ultrasound screening of mammography negative dense breast contributed an additional 20% cancer detection rate in asymptomatic women compared to mammography alone with a higher contribution among women younger than 50 years old.57, level III

11

In another cross-sectional study (n=999 symptomatic women) on the complementary role of ultrasound to mammography, the sensitivity of mammography was 56.6% (95% CI 44.3 to 64.2) while the sensitivity of adjunct ultrasound was 80.8% (95% CI 70.5 to 86.9). Adjunct ultrasound was found to be significantly more sensitive in cancer detection compared to mammography alone (p < 0.001). There was no significant difference in specificity of adjunct ultrasound versus mammography alone. The specificity of mammography was 99.4% (95% CI 98.6 to 99.8) while the specificity of adjunct ultrasound was 99.1% (95% CI 98.85 to 99.6).58, level III

Results of the first year screen in the American College of Radiology Imaging Network (ACRIN 6666) comparing screening breast ultrasound and mammography to mammography alone in women with high risk of breast cancer, the diagnostic yield of mammography was 7.6 per 1000, mammography and ultrasound was 11.8 per 1000 with a supplemental yield of 4.2 per 1000 (95% CI 1.1 to 7.2). The diagnostic accuracy of mammography alone was 0.78 (95% CI 0.67 to 0.87) but higher for mammography and ultrasound at 0.91 (95% CI 0.84 to 0.96). The PPV of biopsy recommendation after full workup of mammography was 22.6% (95% CI 14.2 to 33), ultrasound alone was 8.9% (95% CI 5.6 to13.3) and combined ultrasound and mammography was 11.2% (95% CI 7.8 to 15.6).59, level III

In a study by Bhate et al. on 203 symptomatic women, ultrasound was offered to all women and for those above 35 years old, an additional mammography was also performed. The study found that mammography led to a diagnosis of breast cancer in 4.4% of women. The study also recommended ultrasound to be the initial assessment in the evaluation of symptomatic women below the age of 35 years old instead of 40 years old.60, level III

RECOMMENDATION

Patients presenting with a breast symptom should be evaluated with a full clinical examination, mammography and/or ultrasound followed by biopsy, either fine needle and/or core biopsy. (Grade C)

Adjunctive ultrasound assessment improves breast cancer detection in women of all ages and where possible should be offered to all symptomatic breast patients. (Grade C)

In young women ( < 35 years old), ultrasound should be used as the initial imaging modality as part of the triple assessment. (Grade C)

12

4.3 Pre-operative Assessment of the Breast

4.3.1 Pre-operative Magnetic Resonance Imaging of Early Breast Cancer

In a woman with early or locally advanced breast cancer, MRI may be considered if there is a likelihood that it can lead to a change in surgical management.61

Effective assessment prior to primary treatment ensures appropriate treatment. Pre-

operative MRI has been suggested to be potentially useful in selected clinical situations.

The Belgian guidelines reported that MRI is a sensitive procedure for the diagnosis

of breast cancer with sensitivities ranging from 86 - 98%. However the low quality of

evidence does not advocate the routine use of MRI for the diagnosis and staging of breast

cancer.55

Similarly, the New Zealand guidelines concluded that MRI demonstrates some benefits

in accuracy over conventional imaging modalities. This may lead to change in surgical

management with more extensive tissue removal although subsequent pathology may not

always justify the MRI result.61

In a recent prospective cohort (n=349) of women with invasive breast cancer who were

eligible for breast-conserving therapy, pre-operative contrast enhanced magnetic MRI of

the breast which influenced the rate of incomplete tumour excision. MRI detected larger

extent of breast cancer in 19 women (11.0%) leading to treatment change [mastectomy

(8.7%) or wider excision (2.3%)]. This study concluded that pre-operative MRI did not

significantly (p = 0.17) affect the overall rate of incomplete tumour excision. However

in women with Invasive Ductal Carcinoma (IDC), pre-operative MRI yielded significantly

(p = 0.02) lower rates of incompletely excisions.62 level II-2

In a retrospective study (n =160) of women with operable breast cancer (stages Tis to T4),

an additional 30 cases (18.75%) were diagnosed correctly using pre-operative MRI, which

went undetected by clinical palpation, mammography, and breast ultrasound. However 14

cases (8.75%) turned out to be false positive. It was concluded that preoperative breast

MRI detects additional invasive carcinoma and changes surgical management of operable

breast cancer.63, level III

13

The New Zealand guidelines recommended that MRI should be considered in clinical

situations where other imaging modalities are unreliable or inconclusive. These include:

invasive lobular cancer; suspicion of multicentricity; genetic high risk (BRCA1 or BRCA2);

patients with T0 N+ disease; patients with breast implants/foreign bodies; diagnosis of

recurrence; follow up of neo-adjuvant treatment; women with dense breasts.61

RECOMMENDATION

MRI should not be routinely performed in the pre-operative assessment of patients with biopsy proven invasive breast cancer or DCIS. (Grade B)

MRI may be considered in clinical situations where other imaging modalities are unreliable or inconclusive which include:

• Invasive lobular cancer

• Suspicion of multicentricity

• Genetic high risk (BRCA1 or BRCA2)

• Patients with T0 N+ disease

• Patients with breast implants/foreign bodies

• Diagnosis of recurrence

• Follow up of after neo-adjuvant treatment

• Women with dense breasts (Grade B)

14

5. BASELINE STAGING INVESTIGATION

The American Joint Committee on Cancer (AJCC) Cancer Staging Manual (7th Edition) has been used for staging of cancers in these guidelines. (Refer to Appendix 3)64,

5.1 Early Breast Cancer

Early breast cancer is breast cancer that has not spread beyond the breast or the axillary lymph nodes. This includes ductal carcinoma in situ and stage I, stage IIA and stage IIB.

The Belgian guidelines concluded that there is no good evidence to support routine screening for metastases for patients with early breast cancer who are asymptomatic and with negative clinical findings. Although the imaging modalities such as chest x-ray (CXR), liver ultrasound and bone scintigraphy are relatively inexpensive, these imaging are not recommended for asymptomatic women with intra ductal tumour, pathological stage I disease and early operable breast cancer (T1-2, N0-1).55

Imaging investigations including CXR, bone scan, liver ultrasound and computerised tomography (CT) scan have low diagnostic yields and should be used only when clinically indicated such as symptoms of lung disease, a palpable liver, abnormal liver function test, bone pain or bony tenderness.61

The New Zealand guidelines recommended that patients with symptoms or positive clinical findings of metastases at a particular site will need appropriate investigation. In addition, in those with more advanced but operable disease (T3, N1-2) or in whom neo-adjuvant treatment is considered, further investigation is needed to exclude distant metastases. Patient at high risk of harbouring distant metastases (such as triple negative patients and young patients < 35 years old) should also be staged aggressively. However, these guidelines did not recommend routine bone scintigraphy for patients presenting with metastatic disease if CT of the thorax, abdomen and pelvis had been performed. Bone scintigraphy should be reserved for patients with symptoms suggestive of bone metastases at sites not imaged by CT and who had normal plain films of the symptomatic sites. There is insufficient evidence to determine whether fluorodeoxyglucose -positron emission tomography (FDG-PET) or bone scintigraphy is superior in detecting osseous metastases from breast cancer. However FDG-PET had a higher specificity and might better serve as a confirmatory test.61

A retrospective study (n=221) of patients with primary operable breast cancer showed that routine pre-operative staging with bone scan and liver ultrasound were not helpful. Bone scan had a false positive value of 12% and PPV of 19% while liver ultrasound had a false positive value of 3% and PPV of 33%. The author concluded that these investigations should be reserved for patients with symptoms suggestive of metastases, abnormal blood test and high risk patients.65, level III

15

RECOMMENDATION

In patients with early asymptomatic operable breast cancer, intraductal tumour and pathological stage I, screening (CXR, liver ultrasound, CT scan and bone scintigraphy) for metastasis should not routinely be performed. (Grade C)

In patients presenting with symptoms suggestive of bone metastases, bone scintigraphy should be used if CT of the thorax, abdomen and pelvis or plain radiograph of the symptomatic site are negative. (Grade C)

5.2 Advanced Breast Cancer

Locally advanced breast cancer (LABC) includes breast cancers with large primary tumors of more than 5 cm or those with skin and/or chest wall involvement, and with or without regional lymph node involvement (Stage 3a, 3b and 3c).

If advanced breast cancer is suspected either clinically or on initial imaging, the routine practice is to confirm the diagnosis and to assess the extent of the metastatic disease with more imaging (staging). This includes assessment of bony and visceral metastases such as plain radiograph, ultrasound, bone scintigraphy, CT, MRI and positron emission tomography/computerised tomography (PET/CT).66

MRI and FDG-PET were equal to or better than scintigraphy in visualising osteolytic bone metastases rather than osteoblastic lesions. Whole body MRI was found to be better than FDG-PET in detecting distant metastases particularly in the abdominal organs, brain and bone.66

There is insufficient evidence to support the choice of one imaging modality over another. The choice of the modality will depend on the availability of resources.66

RECOMMENDATION

In patients presenting with clinically advanced breast cancer, further imaging modalities such as chest x-ray, liver ultrasound, and/or CT scan should be offered to assess the extent of disease depending on the available resources. (Grade C)

CT (with bone window) or MR or bone scintigraphy may be offered to assess presence and extent of metastases in the axial skeleton. (Grade C)

The risk of pathological fracture in the extremities may be assessed using bone scintigraphy and/or plain radiography. (Grade C)

16

5.3 Positron Emission tomography (PET) or PET/CT in Staging

Unlike other imaging modalities, FDG labelled with positron emitting flourine provides functional information. Most malignant tumours have a higher glucose metabolism than normal tissue and take up more FDG-PET. Therefore, they show up as areas of increased activity. When CT is fused with PET, functional information can be located anatomically.66

The NICE guidelines recommended that PET/CT should only be used to make new diagnosis of metastases for patients with breast cancer whose imaging is suspicious but not diagnostic of metastatic disease54. Whereas, the New Zealand guidelines recommended PET scan as a confirmatory test in diagnosing bony metastases as it was noted that PET scan had a higher specificity compared to bone scintigraphy.61

PET scan is not indicated in the diagnosis of breast cancer, axillary staging and in the follow-up of breast cancer. However, PET scan can be useful for the evaluation of metastatic disease in invasive breast cancer.55

A cross-sectional study (n=183) evaluated the preoperative diagnostic accuracy between FDG-PET/CT and axillary ultrasonography (AUS) in detecting axillary lymph node metastasis primary operable breast cancer. The diagnostic accuracy of FDG-PET/CT was shown to be nearly equal to AUS in terms of sensitivity (64.4% vs 54.2%), specificity (94.4% vs 99.2%) and overall accuracy (84.7% vs 84.7%). However the author concluded that considering the limited sensitivities, the high radiation exposure by FDG-PET/CT and costs of the examination, AUS is a more cost-effective imaging tool.67, level III

A prospective study (n=80) showed that the sensitivity, PPV and accuracy of FDG-PET for the detection of axillary lymph node metastasis were 44%, 89% and 72% respectively. It was concluded that FDG-PET could not replace histological staging using sentinel lymph node biopsy (SLNB) in patients with breast cancer.68, level II-2

In a retrospective study by Taira et al. (n=90) it was found that the positive detection rate on FDG-PET/CT was insufficient to determine the indication for sentinel node biopsy (sensitivity 48%, specificity 92%, PPV 72% and NPV 81%).69, level III

Another retrospective study (n=46) evaluated the role of PET/CT for tumour staging and recurrence. It demonstrated that the accuracy of diagnosis of tumour recurrence by PET/CT is 83% for patient-based and 96% for site-based. It was concluded that PET/CT was a sensitive and an accurate imaging modality, superior to CT for the diagnosis of tumour recurrence and for the definition of extent of disease.70, level III

17

A comparative study (n=34) of women with increased tumour markers showed that the combination of PET/CT was superior to PET or CT alone. CT had sensitivity of 92% and specificity of 78%, PET had a sensitivity of 88% and specificity of 78%, and combination of PET/CT sensitivity was 96% and specificity at 89%.71, level II-3

PET/CT was superior to conventional imaging procedures for detection of distant metastases. Although FDG-PET and CT provided similar diagnostic accuracy, this was often found to be complementary. This study demonstrated that for conventional imaging the sensitivity was 43% and specificity was 98% whereas, CT had a sensitivity of 83% and specificity of 85%, and FDG-PET had a sensitivity of 87% and specificity of 83%.72 , level III

Tevfik carried out a study on 271 women with biopsy-proven primary breast cancer looking at the efficacy of FDG-PET in detecting primary tumour, axillary lymph node and distant metastases. It was found that there was variation in diagnostic accuracy based on tumour size. The sensitivity increased with increasing tumour size i.e. T1a at 53%, T1b at 63%, T1c at 80% and T2 & T3 at 92%. For axillary lymph node metastasis, the sensitivity was 41% in pN1, 67% in pN2 and 100% in pN3, while specificity was 89% for pN0 stage. It was concluded that FDG-PET could detect axillary lymph node metastases in high axillary node stages.73, level II-3

A study done by Huang et al. on the estimation of radiation dose and cancer risk for whole body PET/CT scanning for the Hong Kong and U.S population showed that the effective dose for protocol A, B and C were 13.45, 24.79 and 31.91mSV for female and 13.65, 24.80 and 32.18mSv for male patients. The lifetime attributable risks (LARs) for cancer incidence were between 0.231% and 0.514% for a 20 years old U.S. woman and between 0.163% and 0.323% for 20 years old man. LARs was 5.5% - 20.9% higher for the Hong Kong population. This was attributed to a longer life expectancy and higher baseline cancer incidence in the organs sensitive to radiation in Hong Kong population. The induced cancer risks decreased when age at exposure increased. PET/CT examination resulted in increased patient radiation exposure compared to stand alone PET or CT examination, as the effective dose was the combination of the dose from PET and CT.74, level III

RECOMMENDATION

PET or PET/CT scan should not be offered to make the diagnosis of malignancy in breast tumours or for axillary staging or in the follow up of breast cancer patients. (Grade C)

PET/CT scan may be used in patients whose imaging is suspicious but not diagnostic of metastic cancer. (Grade C)

18

6. LABORATORY DIAGNOSIS

6.1 Fine Needle Aspiration Cytology (FNAC) vs Core Biopsy (CB)

A retrospective study of screen detected breast cancers (n=763) found that combining FNAC and CB resulted in improvement in accuracy, when the sensitivity increased from 93% for CB alone to 98% for combined FNAC and CB. This study concluded that combined FNAC and CB may be offered for diagnosis of breast cancer where facilities and expertise are available.75, level III

In contrast, an earlier comparative study of symptomatic patients (n=112) found that FNAC when performed in addition to CB did not provide useful additional information (sensitivity for FNAC was 90% and CB was 99%). The authors concluded that CB had a high accuracy rate which could not be improved upon by adding FNAC.76, level III

A prospective study of suspicious breast lesions (n=264) showed that FNAC and CB had similar accuracy rates when the lesions were ≤ 2 cm or ≥ 5 cm in size (sensitivity for FNAC was 85.6% and CB was 88.3%). This study also concluded that for lesions between 2 - 5 cm, CB was more accurate than FNAC (sensitivity for FNAC was 89.1% and for CB was 92.4%). However when combined, FNAC and CB had a sensitivity of 97.5%.77, level II-3

A comparative analysis of CB and FNAC (n=50) for breast cancer (clinically or mammographically detected) revealed that sensitivity for FNAC was 78.15% and CB 96.5% while specificity for FNAC was 94.44% and CB was 100%. However, CB had a higher inadequate sample rate. Thus the authors concluded that FNAC and CB cannot be treated as mutually exclusive, but must complement each other. While FNAC may be the preferred initial procedure to obtain diagnostic information, CB may be appropriate for impalpable breast lesions.78, level II-3

A locally conducted retrospective study (n=436) on the method of initial diagnosis in breast cancer showed that the accuracy of FNAC was 87% versus CB of 99%. However the author concluded that the ideal method of biopsy is dependent on the physical characteristics of the lump as well as the expertise available locally. Therefore FNAC was a reliable and relevant method for diagnosis of breast cancer and CB may be used as a second line method for diagnosis. Excision should be considered as the last option.79, level III

In a study (n=39) using concurrent trucut biopsy and FNAC for breast cancer, it was demonstrated that FNAC had a statistically significant higher detection rate compared to CB (90% vs 67%, p <0.02). There was no false negative in FNAC. A total of nine cases reported positive in FNAC were negative in CB. The authors were of the opinion that CB was technically more difficult to perform with higher morbidity.80, level III

19

RECOMMENDATION

Fine needle aspiration cytology may be considered as the initial method of pathological assessment for palpable breast lumps where facility and expertise are available. (Grade C)

Core biopsy may be used as a complement for pathological diagnosis if the fine needle aspiration cytology is equivocal. (Grade C)

Core biopsy in combination with Fine needle aspiration cytology may be used where facility and expertise are available. (Grade C)

6.2 Human Epidermal Growth Factor Receptor 2 (HER-2) Testing In Breast Cancer

HER-2 testing may be performed by various methods including immunohistochemistry (IHC), fluorescent in-situ hybridisation (FISH), chromogenic in-situ hybridisation (CISH) and silver-enhanced in-situ hybrid (SISH).

A technology review based on 10 studies looking at HER-2 testing showed that the most cost-effective testing strategy is to screen all breast cancer cases with IHC, followed by FISH or CISH for IHC of 2+ (or of 2+ and 3+). FISH testing was more objective and predictive of response to anti-HER-2 therapy and had been advocated to confirm some or all positive IHC results. CISH is another promising and practical alternative to FISH that can be used in conjunction with IHC. Thus, it may represent an important addition to the HER-2 testing algorithm.81, level III

In a more recent study (n=72) by Pederson et al., dual CISH (using probe for HER-2 and centromere of chromosome 17) was shown to have 98.6% concordance and a correlation coefficient of 0.95 with FISH. The author concluded that further evaluation of its accuracy is still required before adopting into routine practice.82, level III

In another study (n=230), SISH was found to be an alternative for HER-2 testing. It had 96% concordance with CISH.83, level III

RECOMMENDATION

HER-2 test using immunohistochemistry should be performed for all invasive breast cancer cases. (Grade C)

Fluorescent in-situ hybridisation, silver-enhanced in-situ hybrid or chromogenic in-situ hybridisation should be used for confirmation when the immuno-histochemistry score is 2+ or 3+. (Grade C)

20

6.3 Pathology Reporting for Breast Cancer

An adequate pathology report for breast cancer must have the following minimum parameters: modified from 84, level III

• Location (side and quadrant), maximum diameter, multifocality

• Tumour type (histology)

• Histological grade

• Lymph node involvement and total number of nodes examined

• Resection margins

• Lymphovascular invasion

• Non-neoplastic breast changes

• Hormone receptor status [estrogen-receptor/progesterone receptor (ER/PR)]

• HER-2 assessment

An audit (n=120) demonstrated that majority of the pathology reports did not fulfil the criteria set by College of American Pathologists.85, level III

In another audit conducted in Queensland looking at completeness of randomly selected histopathology reports (n=440) of newly diagnosed breast cancer, it was noted that 88% of synoptic (checklist) reports had all 7 criteria whereas only 27% of non-synoptic (free text format) reports had the same. Usage of synoptic reporting in laboratories varied depending on the workload (low at 82%, medium at 82% and high at 64%).84, level III

Similarly, an audit (n=100) done in the United Kingdom showed that the introduction of a standard proforma, that included 18 criteria outlined in the Royal College of Pathologists Minimum Dataset for breast cancer reports, led to a significant improvement (p < 0.001) in the completeness of breast cancer histopathology report (74% in the proforma versus 34% in the free text group).86, level III

RECOMMENDATION

A complete pathology report should have a minimum dataset.* (Grade C)

*Refer to Appendix 4 for detail

21

7. TREATMENT OF BREAST CANCER

7.1 Surgical Management for Women with Early Breast Cancer

Surgery is the mainstay of treatment for early breast cancer and consists of either breast conserving surgery (BCS) or mastectomy, and assessment of axillary lymph node.

A SR which included six randomised controlled trials (RCTs) with a 15 years follow up concluded that BCS and radiotherapy offer the same survival benefits as modified radical mastectomy in women with early breast cancer. (no significant differences in overall survival and disease free survival). Other outcome measures showed no evidence for a substantial difference in post-operative psychological health between women who have had either modality.61

RECOMMENDATION

All women with early breast cancer should be undergoes breast conserving surgery or mastectomy to obtain clearance of the cancer from the breast. (Grade A)

7.2 Contraindications of Breast Conserving Surgery (BCS)

Contraindications of BCS:

• The ratio of the size of the tumour to the size of the breast and location of the tumour would not result in acceptable cosmesis

• Presence of multifocal/multicentric disease clinically or radiologically

• Conditions where local radiotherapy is contraindicated (such as previous radiotherapy at the site, connective tissue disease and pregnancy)

BCS is increasingly accepted as a surgical technique for treatment of breast cancer since its introduction. However, mastectomy is required if there are absolute contraindications to BCS.

Six RCT recommended that BCS and radiotherapy were contraindicated if the ratio of the size of the tumour to the size of the breast would not result in acceptable cosmesis, if there are any contraindications to radiotherapy and presence multicentric/multifocal tumour.61

22

A retrospective study (n=1485) found that there was no difference in overall survival and disease free survival between BCS and mastectomy in centrally located tumours. In the same study, no difference was seen in BCS between centrally located tumour and peripheral tumours. 87, level II-2

RECOMMENDATION

Breast conserving surgery is an option for a woman with a centrally located tumour, although it may require excision of the nipple and areola, which may compromise cosmesis. (Grade A)

7.3 Tumour Free Margin in Breast Conserving Surgery (BCS)

If the surgical margin is less than 2 mm, several factors should be considered in determining whether re-excision is required. These includes:

• Age

• Tumour histology (lymphovascular invasion, grade, extensive in-situ component and tumour type such as lobular carcinoma)

• Which margin is approximated by tumour (smaller margins may be acceptable for deep and superficial margins)

• Extent of cancer approaching the margin

Complete excision reduces the risk of local recurrence. However, there is an on-going debate on the optimal tumour free margin.

A SR revealed limited evidence in the optimal tumour free margin. There was no consistency regarding the optimal tumour-free tissue margin. There was an ongoing, unresolved debate about how great a margin of excision is necessary, particularly as there are no good RCTs that answer this question. However, there was clear evidence that leaving involved margins results in unacceptably high local recurrence rates.61

NICE evaluated a few RCTs and concluded that the crude local recurrence rate was 20 - 38% for margin 1 mm or less and 13 - 34% for a margin 2 mm or less. This crude local recurrence rate reduced to 13 - 19% with the addition of radiotherapy to 1 - 2 mm a margin. However, when a margin of 2 mm or more were achieved, the local recurrence rate was 2% (with radiotherapy) and 11% (without radiotherapy). This examination did not include the skin/superficial margin and fascial/deep margin as it may be impossible to obtain a 2 mm clearance.54

23

RECOMMENDATION

Complete excision of the tumour with clear margin (greater than or equal to 2 mm) is advised in breast conserving surgery. (Grade A)

7.4 Axillary Surgery in Early Breast Cancer

Axillary lymph node dissection (ALND) comprises of removal of one, two or three level of nodes relative to the pectoralis minor muscle. Typically 10 - 15 lymph nodes are retrieved and at least one section from each assessed by standard haematoxylin and eosin (H&E).54

The New Zealand guidelines highlighted the importance of accurate assessment and management of the axillary nodes in women with early breast cancer. The assessment should be undertaken for most early invasive breast cancers in order to stage the disease, minimise the risk of loco-regional recurrence and assist in planning of adjuvant therapy. Several adverse events are associated with the management of the axilla and women should be advised of the benefits and potential harms associated with each procedure. Axillary node dissection is more effective at lowering the risk of local recurrence than axillary node sampling, which in turn is more effective than no axillary surgery. No evidence was identified on the effectiveness of excision of the supra-clavicular and internal mammary chain nodes compared with no excision. 61

7.4.1 Indications for Sentinel Lymph Node Biopsy (SLNB) in Breast Cancer

The New Zealand guidelines concluded that SLNB was an appropriate method of staging the axilla as there was no difference in axillary recurrence or overall survival. There was limited or no trial data available on the effectiveness of SLNB vs axillary lymph node dissection in the following subgroups:

• Women with tumours > 3cm

• Women with multicentric/multifocal tumours

• Women with clinically positive nodes

• Pregnant or breastfeeding women

• Women with known allergies to radioisotopes or blue dye

• Women with previously treated breast cancer or axillary surgery on the affected side

24

A woman should be informed of the potential for an unsuccessful SLNB or a false negative result.61

NZGG reviewed NBOCC guidelines and one SR and concluded that SLNB should be performed by surgeons who are trained and experienced in the SLNB. Another trial noted that the accuracy increased and false negative decreased when the surgeon performed 30 or more procedures.61

Apart from that, based on the same guidelines that included four RCTs and one SR evaluating technical aspect of SLNB, NZGG reported that combination radioisotope and blue dye is associated with a higher rate of sentinel lymph node detection than blue dye method alone.61

RECOMMENDATION

Sentinel node biopsy should not be carried out in women with clinically involved nodes. The safety and efficacy of sentinel node biopsy for breast cancer > 3cm or multifocal disease has yet to be demonstrated in randomised controlled trials. As such, it is not recommended for these groups. (Grade A)

Sentinel lymph node biopsy may be offered to the following :

• Unifocal tumour of ≤ 3cm

• Clinically non-palpable axillary nodes (Grade B)

Sentinel lymph node biopsy should only be performed by surgeons who are trained and experienced in the technique.(Grade A)

Dual technique with isotope and blue dye in performing the sentinel lymph node biopsy is preferred. (Grade A)

7.5 Immediate Breast Reconstruction vs Delayed Breast Reconstruction

The choice of immediate or delayed reconstruction should be discussed within the team and with the patient.

There is very limited high quality evidence to address this issue whether the timing of breast reconstructive surgery alter the local recurrence rate and overall survival. However based on the NICE guideline, there is no difference in recurrence and survival following mastectomy with immediate reconstruction compared to mastectomy with no reconstruction.54 Based on observational studies, breast reconstruction does not appear to be associated with an increase in the rate of local cancer recurrence or to impede the ability to detect recurrence if it develops. 61

25

Expert opinion from NZGG Development Group noted that radiotherapy to the reconstructed

breast may result in significantly worse cosmetic outcome, especially when an implant

had been used.61

A retrospective study carried out in the MD Anderson Cancer Centre showed that of 32

patients who had radiation therapy after immediate free transverse rectus abdominis

myocutaneous (TRAM) flap reconstruction had 87.5% of late complications compared to

8.6% in the 70 patients who had delayed free TRAM flap reconstruction after radiotherapy.

Distorted contour due to flap contraction from radiation therapy required re-operation

in 28% of these patients. These findings indicate that, in patients who are candidates

for free TRAM flap breast reconstruction and need post-mastectomy radiation therapy,

reconstruction should be delayed until radiation therapy is complete.88, level III

A retrospective review of 224 pedicled TRAM flaps reconstructions in 200 patients over a

10 year period found that active or former smoking and obesity contribute to a significant

complication rate.89, level III

The Michigan Breast Reconstruction Outcome Study, a prospective cohort study of 326

patients, found that the most significant factors associated with higher complication

rates were timing of reconstruction and body mass index. Both immediate breast

reconstruction and obesity were associated with higher and major complication rates.

The type of reconstruction, whether implant, pedicled TRAM or free TRAM, had no effect

on complication rate.90, level II-2

The aim of immediate breast reconstruction is to improve well-being and quality

of life for women undergoing mastectomy for breast cancer. A prospective study

used the SF-36 Health Survey questionnaire to assess quality of life before and

12 months after mastectomy and immediate breast reconstruction together with

patients’ expectations of and satisfaction with the immediate breast reconstruction

with implant. Scores for 76 participants were compared with those in 920 age-

matched women from the general population. Pre-operative scores for emotional

well-being and physical role functioning were lower than in the reference population,

while after 12 months the scores in all domains had improved and were comparable

with those in the reference population. Although many factors may influence quality

of life, one year after breast cancer surgery with immediate reconstruction scores

were equivalent to those of the normal population.91, level II-2

26

Two groups of consecutive patients from two different plastic surgical practice populations were evaluated to determine psychosocial differences between those who underwent immediate (n = 25) vs delayed (n=38) breast reconstruction. The relationship between timing of reconstruction and self-reported distress over the mastectomy experience revealed that only 25% of the women who underwent immediate repair reported “high distress” in recalling their mastectomy surgery compared with 60% of the delayed reconstruction group (p = 0.02).92, level II-2

RECOMMENDATION

Caution is required before offering immediate breast reconstruction to women who are active smokers or obese. (Grade C)

Discuss immediate breast reconstruction with all patients who are being advised to have a mastectomy and offer it except where significant co-morbidity or (the need for) adjuvant therapy may preclude this option. (Grade C)

In patients who are candidate for free flap breast reconstruction and need post-mastectomy radiation therapy reconstruction should be delayed until radiation therapy is completed. (Grade C)

7.6 Management of Locally Advanced Breast Cancer

7.6.1 Neo-Adjuvant chemotherapy in Locally Advanced Breast Cancer

Locally advanced breast cancer is invasive breast cancer that has one or more of the following features:

• large (typically bigger than 5 cm)

• spread to several lymph nodes in the axilla or other areas near the breast

• spread to several lymph nodes in the axilla such as the skin, muscle or ribs

However, there are no signs that the cancer has spread beyond the breast region or to other parts of the body.

The NICE guidelines found that there was no significant difference in overall survival (OS) and disease free survival (DFS) between neo-adjuvant chemotherapy and post-operative chemotherapy. However, better tumour response to chemotherapy was associated with better outcomes. The NICE guidelines also conclude that while giving neo-adjuvant chemotherapy to locally advanced breast cancer (LABC), adequate long-term local control by surgery and/or radiotherapy is still essential including those patients with complete clinical response. Many retrospective reviews suggest that radiotherapy reduces locoregional recurrence and improves survival in patients following neo-adjuvant chemotherapy and mastectomy.54

27

A study showed that neo-adjuvant chemotherapy can be given to downsize the tumour in an attempt for BCS or enable subsequent surgery for initially inoperable breast cancer. In addition to improving both operability and rates of BCS, neo-adjuvant chemotherapy also provides a valuable window to assess disease response to treatment and perform correlative tissue analyses.93, level I

7.6.2 Factors Affecting Response to Neo-Adjuvant Chemotherapy

Neo-adjuvant chemotherapy or primary systemic therapy is an established option for most patients with LABC. It is primarily utilised to optimise surgical outcomes for women with LABC.

A SR concluded that neo-adjuvant chemotherapy gives better clinical and pathological response in ER-negative tumours. Combinations of taxanes and anthracycline and the use of biological response modulators (herceptin) give high pathological complete responses (pCR) in HER-2 positive tumours. Other characteristics of tumours which respond well to chemotherapy include the non-lobular type, high grade histology, high Ki67 and luminal B. These tumour types have a higher chance of response and should be considered for neo-adjuvant chemotherapy. In contrast, tumours which show low response to chemotherapy (such as lobular type and low Ki67) should be considered for alternative approaches (such as neo-adjuvant endocrine therapy or mastectomy as initial treatment).94, level I

RECOMMENDATION

Neo-adjuvant chemotherapy or pre-operative systemic therapy can be offered to patients with operable locally advanced breast cancer who are not suitable candidates for BCS at presentation. (Grade A)

In locally advanced breast cancer that is inoperable, neo-adjuvant chemotherapy should be given to downsize the tumour to enable subsequent surgery. (Grade A)

7.7 Surgery for the Primary Tumour in Metastatic Breast Cancer

There is no RCT addressing surgery for the primary tumour in metastatic breast cancer. However, one retrospective study showed that surgical removal of the primary tumour was associated with a significantly longer survival time in patients with distant metastatic disease at diagnosis with 5-year survival rates of 24.5% with mastectomy and 13.1% without mastectomy (p < 0.0001).95, level II-3

28

Another retrospective study (n=111) concluded that improvement in local control may play a role in improving outcomes in women with stage IV breast cancer, and resection of in-breast tumours can help to achieve this.96, level III

RECOMMENDATION

Surgery of the primary tumour may be considered in stage IV breast cancer. (Grade C)

7.8 Resection of Metastases in Metastatic Breast Cancer

NICE guidelines concluded that there was no good evidence on the surgical treatment of metastatic brain disease from breast cancer. However, the guidelines suggested surgical therapy followed with whole brain radiotherapy in patients with single or small number of potentially resectable brain metastases, having good performance status and with no or well-controlled other metastatic disease.66, level I

For lung and liver metastasis, retrospective studies concluded that there was may be an overall survival benefit in selected cases. Yashimoto et al. had retrospectively followed up 90 patients who had surgery for lung metastases and concluded that surgery may benefit those with early breast cancer, disease free interval of more than three years and lesions of less than 2 cm.97, level III

Two small studies looking at liver metastasis from breast cancer showed no benefit in overall survival in patients with synchronous tumours, a short disease free interval and patients with an aggressive cancer.98, level III; 99, level III

RECOMMENDATION

Resection of limited metastastic disease may be considered in patients with advanced breast cancer in selected cases. (Grade C)

7.9 Systemic Therapy

7.9.1 Indications and Benefits of Adjuvant Chemotherapy in Early Breast Cancer

Breast cancer is recognised as a systemic condition even in early stage of the disease, with a significant risk of distant micro-metastases. As a result, adjuvant chemotherapy has an established role in eradicating these micro-metastases, thus improving survival.

29

NICE guidelines did not specifically address this issue in its current edition as adjuvant chemotherapy is widely accepted internationally to be of significant proven benefit in women with breast cancer. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis of 194 un-confounded randomised controlled trials of adjuvant chemotherapy and hormonal therapy indicated that the use of anthracycline-based adjuvant chemotherapy is associated with a reduction 38% in the annual breast cancer death rate for women younger than 50 years of age and 20% for those between 50 and 69 years when diagnosed. The absolute benefit of chemotherapy varies according to patient age and underlying risk of recurrence. An estimate of the benefit of adjuvant chemotherapy can be made from the EBCTCG data [refer table 4].54

Table 4: Estimate of Benefit of Adjuvant Chemotherapy

Age Risk Absolute survival difference

Number needed to treat (NNT)

< 50 Low 4.6% 22

< 50 Intermediate 8.7% 12

< 50 High 15.1% 7

50 - 69 Low 2.4% 42

50 - 69 Intermediate 4.4% 23

50 - 69 High 7.4% 14

Adapted from EBCTCG Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an observation of RCT. Lancet 2005; 365: 1687-1717

The advantage of adjuvant chemotherapy in post-menopausal patients is of smaller magnitude. The decision should be made after discussion with the patient and her family bearing in mind her age, co-morbidity, performance status & risk stratification (refer Table 5).

Table 5: Stratification for low, intermediate and high risk St. Gallen 2007

Low risk Intermediate risk High risk

pN0 and all of the following criteria:• size of tumour max 2 cm• Grade 1• no vessel invasive• ER-/PR-positive• HER-2 negative• Age ± 35 years

pN0 and at least 1 further criterion:• size of tumour > 2 cm• Grade 2/3• vessel invasion • HER-2 overexpression• age < 35 years old• pN+ (N1-3) and HER-2

negative

pN+ (N1-3) and HERs overexpression or pN+ (N >or =4)

Adapted from Persing, M., and Große R. Current St. Gallen Recommendations on Primary Therapy of Early Breast Cancer. Breast Cancer. 2007; 2: 137-40

30

RECOMMENDATION

Adjuvant chemotherapy should be considered in all patients with early breast cancer. (Grade A)

Adjuvant chemotherapy should be offered to all women with any of the following risk factors especially in pre-menopausal women:

• Oneormorepositiveaxillarylymphnodes

• ERnegativedisease

• HER-23+disease

• Tumoursize>2cm

• Grade3disease(Grade A)

7.9.2 Indications and Benefits for Neo-Adjuvant Chemotherapy Compared to Adjuvant Chemotherapy in Early Breast Cancer

There is an option to offer chemotherapy prior to surgery in early breast cancer. This has the theoretical advantage of eradicating micro-metastases earlier in the course of the disease, in addition to the possibility of breast conserving surgery as opposed to mastectomy.

NICE guidelines commented on two SR. The first one, by Meiog 2007, reviewed ten RCTs involving 4,620 patients. The review did not find any difference in overall survival (HR=0.98, 95% CI 0.87 to 1.09). The subsequent SR by Rastogi 2008 also did not find any improvement in overall survival with neo-adjuvant compared to adjuvant chemotherapy (HR=0.99, 95% CI 0.85 to 1.16). However, in patients with locally advanced breast cancer who received primary chemotherapy, findings from a Cochrane SR and two other SRs suggested that better tumour response was correlated with better outcome. The applicability of these findings is limited because the majority of the patients had stage I and II disease. Pre-operative chemotherapy can be offered to those who are considering BCS. However, local recurrence is higher compared to mastectomy and this should be discussed with the patient. Seven studies in the SR reported a pathological complete response rate (pCR) of 4 - 29.2% with neo-adjuvant chemotherapy. Four RCTs reported overall survival data for 1,290 assessable patients and involving 381 deaths. There was a statistically significant difference in favour of pCR vs residual disease with HR=0.48 (95% CI 0.33 to 0.69).54

31

Gianni et al. reported on the results of a phase III RCTs evaluating the addition of paclitaxel to doxorubicin and followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy. There was no difference in overall survival between the adjuvant and neo-adjuvant chemotherapy arms in the study (HR=1.10, 95% CI 0.77 to 1.59).100, level I

RECOMMENDATIONNeo-adjuvant chemotherapy should not be routinely given to patients with early breast cancer. (Grade A)

7.9.3 Indications and Benefits of Taxane-Based Regimens Compared to Anthracycline-Based Regimens in Early Breast Cancer

Over the last decade, studies have shown significant benefits of taxane based chemotherapy regimens in metastatic disease. In the effort to further improve outcome in the adjuvant setting, taxanes have been investigated in numerous clinical trials.

NICE guidelines recommended the addition of docetaxel to an adjuvant chemotherapy regimen for patients with lymph node positive breast cancer. This was based on SR and meta-analysis. All of these studies confirmed an improvement in overall survival with the addition of a taxane to the adjuvant chemotherapy regimen.54

Ellis et al. evaluated the benefit of four cycles docetaxel after four cycles of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy compared to eight cycles of FEC or cyclophosphamide, methotrexate, and fluorouracil Epi-(CMF). There was no difference in the five years disease free survival or overall survival despite recruiting 4,162 patients and a high proportion of patients with lymph node positive disease. However, the dose of epirubicin used in this trial was 60 mg/m2 in the experimental arm and 60 mg/m2 or 100 mg/m2 in the control arm. The PACS01 trial assessed as part of the NICE guidelines evaluated three cycles of docetaxel after three cycles of FEC with epirubicin at a dose of 100 mg/m2 and found a survival benefit of 4%.101, level I

Gianni et al. evaluated the addition of paclitaxel to an adjuvant doxorubicin and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen in 904 patients. There was no difference in overall survival (HR=0.80, 95% CI 0.56 to 1.14). However, paclitaxel was given once every three weeks in this trial which is now not considered the optimal method of administering paclitaxel in the adjuvant setting.100, level I

Jones et al. published the updated results of the US Oncology Group study comparing four cycles of docetaxel and cyclophosphamide to doxorubicin and cyclophosphamide. After a median follow-up of 1,016 patients over seven years, there was a statistically significant survival difference in overall survival from 82% to 87% (HR=0.69, 95% CI 0.50 to 0.97).102, level I

32

Goldstein et al. compared doxorubicin and docetaxel to doxorubicin and cyclophosphamide in 2,882 patients and did not find any difference in disease free or overall survival. However, a lower dose of docetaxel (60 mg/m2 every three weeks) was used. Furthermore, 66% of the patients recruited into this study had lymph node negative disease and the median size of the tumour was 2 cm. A suboptimal dose of docetaxel would not be expected to have a significant survival benefit in such a group of patients with good prognosis disease.103, level I

RECOMMENDATION

For women with lymph node positive breast cancer, a taxane (preferably Docetaxel) may be considered in the adjuvant chemotherapy regimen. (Grade A)

7.9.4. Indications and Survival Benefits for Anti-HER-2 Adjuvant Treatment in Early Breast Cancer

HER-2 is a transmembrane epidermal growth factor receptor that plays an important role in the growth signalling pathway for breast cancer. Over-expression of HER-2 or amplification of the gene has been associated with poorer prognosis. Trastuzumab has been shown to improve survival in the metastatic setting. More recent trials in the adjuvant setting have also demonstrated encouraging results.

NICE guidelines recommended the use of trastuzumab (herceptin) for patients with HER-2 3+ early breast cancer. This was based on three RCTs and a meta-analysis. Herceptin Adjuvant (HERA) trial evaluated the sequential use of herceptin after adjuvant chemotherapy in 5,102 women. With a median follow up of two years, a statistically significant improvement in overall survival was observed (HR=0.66, 95% CI 0.45 to 0.87). Romond found a similar improvement in overall survival with the addition of herceptin concurrently with adjuvant chemotherapy (HR=0.67, 95% CI 0.48 to 0.93). Using data from both trials, the NNT at two years was 56 and at three years were 40. The disease free survival was the primary end-point for both trials and this was also statistically significant with a difference of 8.4 - 11.7% at two years. Joensuu investigated nine weeks of herceptin with adjuvant chemotherapy and did not find a difference in overall survival. The meta-analysis included five RCTs and confirmed a overall survival benefit with the addition of herceptin to adjuvant chemotherapy (HR=0.66, 95% CI 0.55 to 0.78). 54

RECOMMENDATION

Trastuzumab should be considered in women with HER-2 over-expressed or HER-2 gene amplified breast cancer having adjuvant chemotherapy. (Grade A)

33

7.10 Endocrine Therapy

7.10.1 Endocrine Therapy in Early Invasive Breast Cancer and Ductal Carcinoma in Situ (DCIS)

Endocrine therapy has a long established role in breast cancer. Over the last decade, it has been demonstrated to be of benefit in only in oestrogen receptor positive cancer.

Tamoxifen has been shown to improve survival in ER positive early invasive breast cancer with 15 years OS advantage of 9.2% (NNT=11). Five years of tamoxifen is superior to two years of tamoxifen.54

NICE guidelines reviewed two RCTs (DCIS-National Surgical Adjuvant Breast and Bowel Project (NSABP) B24 and UKCCCR) on tamoxifen. NSABP B24 showed a reduction in ipsilateral breast cancer where invasive breast cancer events of 2.1% in the tamoxifen arm vs 4.2% in the control arm, HR=0.56 (95% CI 0.32 to 0.95) and NNT=48. No difference in OS was seen. UKCCCR trial showed no difference in breast cancer events or OS. It was concluded that there is insufficient evidence to support the use of tamoxifen in DCIS.54

RECOMMENDATION

Tamoxifen should be offered to all women with ER positive invasive early breast cancer. (Grade A)

Hormonal therapy should not be used routinely in ductal carcinoma in situ. (Grade A)

7.10.2 Ovarian Suppression or Ovarian Ablation in Addition to Standard Adjuvant Therapy Consisting of Chemotherapy and Tamoxifen in Pre-Menopausal Breast Cancer Patients

There are some controversies with respect to the addition of ovarian suppression or ablation to chemotherapy and tamoxifen in pre-menopausal women with breast cancer. Some studies have suggested improved outcomes with this approach which were not confirmed by other investigators.

Based on two meta-analyses, NICE guidelines concluded that there was insufficient evidence to support the routine use of ovarian suppression or ablation in addition to chemotherapy and tamoxifen in pre-menopausal women with ER positive breast cancer. According to a recent meta-analysis there was a modest benefit for luteinizing-hormone-releasing hormone (LHRH) agonist with a HR=0.85 (95% CI 0.73 to 0.99) for death after recurrence in a subgroup analysis. However, tamoxifen was not employed as standard therapy after chemotherapy in several studies. This may have increased the magnitude of the benefit of LHRH agonists.54

34

A RCT of pre-menopausal women (n=910) treated with primary surgery and then offered LHRH agonist goserelin and tamoxifen compared to those who were just offered tamoxifen alone showed no benefit with the addition of goserelin in all events with ARR=2.8% (95% CI -7.7% to 2.0%) and breast cancer death with ARR=2.6% (95% CI -6.6% to 2.1%).104, level I

RECOMMENDATION

Adjuvant ovarian suppression or ablation should not be used routinely in addition to tamoxifen and chemotherapy in pre-menopausal women with ER positive early breast cancer. (Grade A)

7.11 Aromatase Inhibitors

In post-menopausal women, the main source of oestrogens is from the peripheral conversion of androgens by the aromatase enzyme. Inhibition of this enzyme will lead to further reduction in oestrogen level which may be of benefit in patients with oestrogen receptor positive breast cancer.

7.11.1 Benefits of Aromatase Inhibitors vs Tamoxifen in the Adjuvant Setting in Post-Menopausal Breast Cancer Patients

Based on the RCTs included in the NICE guidelines, there is no overall survival benefit with the use of aromatase inhibitors in the adjuvant setting. However, a significant improvement in overall survival was seen for the subset of node-positive patients in the letrozole group in the MA17 extended adjuvant trial (HR=0.61, 95% CI 0.38 to 0.98).54

An SR by Eisen et al. showed a disease free survival benefit for aromatase inhibitors in various upfront, switched and extended adjuvant trials with statistically significant HR ranging from 0.50 - 0.87.54

A durable disease free survival advantage of 4.8% and NNT of 21 was seen in the trial with the longest follow up data. This benefit was consistent with the other large randomised studies.54

RECOMMENDATION

Aromatase inhibitors may be considered as an option in post-menopausal women with ER positive early breast cancer as adjuvant hormonal therapy. (Grade A)

35

7.11.2. Benefits of Aromatase Inhibitors vs Tamoxifen in the Advanced Setting in Post-Menopausal Breast Cancer Patients

Based on a SR of 23 RCTs, there was an overall survival benefit in the use of aromatase inhibitors versus standard endocrine therapy. This was particularly seen in third generation aromatase inhibitors with statistically significant survival benefit (HR=0.87, 95% CI 0.82 to 0.93) and reduced breast cancer mortality (HR=0.91, 95% CI 0.86 to 0.96).66

A RCT (n= 371) with a median follow up of 29 months compared exemestane with tamoxifen as a first-line hormonal treatment of metastatic breast cancer in post-menopausal women. This trial demonstrated a progression free survival benefit of 4.1 months but no overall survival advantage HR=1.04 (95% CI 0.76 to 1.41). However, the author concluded that the follow up may be too short to show an overall survival difference.105, level I

RECOMMENDATIONAromatase inhibitors may be considered as first line hormonal therapy in post-menopausal women with ER positive advanced breast cancer. (Grade A)

7.12 Radiotherapy

7.12.1 Post-Mastectomy Radiotherapy in Breast Cancer

In high risk patients who have had mastectomy, there is a significant risk of loco-regional relapse. Radiotherapy has been shown to improve loco-regional control but controversy existed regarding the survival benefit until recently.

The EBCTCG Overview showed a survival benefit of 4.4% and local control benefit of 17% for node positive patients with the use of adjuvant radiotherapy post-mastectomy. This corresponded with a NNT of 23 for overall survival and 6 for local control. For those with node negative disease, there was a detrimental effect on the overall survival by 4.2% while local control improved by 4%. A meta-analysis by Gebski et al. that included only trials utilising optimal radiotherapy also showed a survival benefit of 6.4% with a NNT of 16. NICE guidelines recommended adjuvant chest wall radiotherapy for those post-mastectomy and at high risk of local recurrence including those with four or more lymph nodes involvement or involved resection margins. It also recommended against adjuvant radiotherapy for those with low risk of local recurrence.54

A recent SR (that included only modern radiotherapy techniques for patients with node negative disease) showed a highly significant improvement in the 10 years locoregional recurrence rate with a hazard ratio of 0.17 and more importantly there was no detrimental effect on overall survival.106, level I

36

RECOMMENDATION

Adjuvant radiotherapy should be offered to the following post-mastectomy patients with:

• ≥ Four lymph nodes

• Positivemargin(Grade A)

Adjuvant radiotherapy can be offered to the following post-mastectomy patients with:

• 1-3lymphnodes(Grade B)

• Nodenegativediseasewithhighriskofrecurrencewithtwoormoreriskfactors such as presence of lymphovascular invasion, tumours greater than 2 cm, grade 3 tumours, close resection margin (< 2mm) and premenopausal status (Grade B)

• T3 and T4 tumours (Grade C)

7.12.2 Radiotherapy Post-Breast Conserving Surgery in Breast Cancer

There is 25 - 35% risk of local recurrence post-breast conserving surgery for breast cancer. Radiotherapy has been shown to significantly reduce this risk.

The EBCTCG SR showed a survival benefit of 8.2% and local control benefit of 30.1% for node positive patients with the use of adjuvant radiotherapy post-breast conserving surgery. This corresponded to a NNT of 13 for overall survival and four for local control. For those with node negative disease overall survival improved by 4.6% (p = 0.06) and local control benefit by 16.1%. The NNT for local control was 7. NICE guidelines recommended breast radiotherapy for those who had breast conserving surgery with clear margins.54

A recent RCT (n = 264) focusing on patients with favourable prognostic features with lower risk of recurrence (patients age older than 40, resection margin of at least 1 cm, tumour size 2 m or smaller, node negative, progesterone receptor positive, well to moderately differentiated, unifocal and low cell proliferation rate) showed an improvement of local control by 15% though there was no significant survival benefit.107, level I

A Cochrane SR on post-operative radiotherapy for DCIS for patients who had BCS showed an absolute reduction of 12% for ipsilateral breast events (DCIS and invasive recurrence). There was no survival benefit for this group of patients.108, level I

RECOMMENDATION

All patients with post-BCS should be offered adjuvant radiotherapy for both invasive breast cancer and ductal carcinoma in situ. (Grade A)

37

8. PSYCHOLOGICAL SUPPORT

8.1 Assessment of Distress

The diagnosis of breast cancer for women is undeniably distressing. In addition to the normal reactions to such a diagnosis, many women experience elevated levels of distress as the illness progresses.

For many women with breast cancer, their anxiety and depression go undetected. According to several RCTs, up to 45% of women diagnosed with breast cancer continue to experience clinical anxiety and depression many months into their illness; their distress, in turn, affects various realms of their illness experience including their physical, psychological and social functioning.109

SIGN guidelines recommended that breast cancer services should routinely screen for the presence of distress and risk factors for very high levels of distress from the point of diagnosis onwards (including during follow up review phases) through routinely administered self-report questionnaires. However, these questionnaires are not recommended for those who are not at high risk of developing emotional distress.109

A cross-sectional study looked at the utility of the Hospital Anxiety and Depression Scale (HADS) in detecting emotional distress among women diagnosed with breast cancer (n = 361). Results showed that HADS was able to differentiate women with major depressive disorders (MDD) from others: detection rate of MDD=0.94 (95% CI 0.91 to 0.97), sensitivity of 0.87 (95% CI 0.70 to 0.95), specificity of 0.85 (95% CI 0.81 to 0.89) and PPV of 0.35.110, level III

Another cross-sectional study (n=204) compared the validity and reliability of HADS and Structured Clinical Interview for DSM Disorders (SCID) in detecting emotional distress in women with breast cancer. For MDD the, area under the curve/AUC (total) was 0.77, AUC (depression) was 0.79 and AUC (anxiety) was 0.72. For Anxiety Disorders (ADs), the AUC (total) was 0.74, AUC (depression) was 0.74 and AUC (anxiety) was 0.70. When compared with SCID, the percentage of cases identified by HADS was 28% for MDD and 22% for ADs.111, level III

Thomas et al. conducted a survey looking at the validity and reliability of HADS (n=242) and Cronbach alpha for the depression subscale was 0.81, for the anxiety subscale was 0.71 and total HADS was 0.85.112, level III

38

A recent survey (n=227) compared Beck Depression Inventory Scale Short Form (BDI-SF) and the HADS in screening for depression in women with advanced metastatic breast cancer. Results showed, using a cut-off of 4, the BDI-SF had a sensitivity of 0.84, specificity of 0.63 and PPV of 0.52. But based on a cut-off of 11 on the HADs, the sensitivity was 0.16, specificity 0.97 and PPV 0.75.113, level III

RECOMMENDATION

Women diagnosed with breast cancer should be screened for emotional distress. (Grade C)

Validated self-assessment psychological tests such as Hospital Anxiety and Depression Scale, administered by a trained personnel may be used to screen for emotional distress at the time of diagnosis. (Grade C)

8.2 Cognitive Behaviour Therapy

Women with breast cancer cope with distress differently. However, a significant number of women fail to use effective coping strategies in dealing with the challenges of living with breast cancer. Research has found that individual therapy, such as Cognitive Behaviour Therapy (CBT), has been found to be useful in helping women to utilise effective coping strategies in dealing with their breast cancer.

SIGN guidelines recommended that CBT should be offered in groups or individual format to selected breast cancer patients with anxiety and depressive disorders. It should be also offered to those with localised, loco-regional and advanced stages of cancer.109

A meta-analysis based on 56 RCTs looked at the moderators of different psychosocial interventions for breast cancer patients. CBT led by psychologists was more effective in individual settings compared to group settings (p < 0.05). CBT was also found to be more effective after surgery or months after initial diagnosis than during medical treatment (p < 0.01).114, level I

An evaluation of a group CBT for women suffering from menopausal symptoms following breast cancer treatment using a single group with pre- and post-treatment assessment showed that scores in depressed mood, anxiety and sleep (WHOQOL) significantly improved, as did aspects of quality of life (SF 36) such as emotional role and limitation, energy and vitality, and mental health. Participants also reported significant reduction in hot flushes and night sweats following treatment (38% reduction in frequency and 49% in problem rating) at 6 weeks. Improvements were even maintained at three months follow up.115, level III

39

RECOMMENDATION

Cognitive behaviour therapy should be offered by trained personnel to women with breast cancers in an individual context, across all stages of disease, particularly for the emotionally vulnerable groups identified by the prior assessment of distress. (Grade B)

Cognitive behaviour therapy should be offered preferably right after diagnosis/surgery or months after diagnosis but not during medical treatment. (Grade C)

8.3 Psychosocial Support

Social support, whether tangible, informational or emotional, is essential for women to adjust to life with breast cancer. Support provided has to gear for the women’s needs. Research has indicated that women who receive quality support have improved physical and emotional outcomes.

According to SIGN, group psychosocial interventions should be offered to women who feel it would suit their needs while supportive expressive therapy should be offered to women with advanced breast cancer.109

A RCT (n=227) was conducted to identify the effects of supportive expressive group therapy (SEGT) for women with metastatic breast cancer on survival and psychosocial outcomes. Ppatients were randomised to either intervention (SEGT and relaxation therapy, n=147) or relaxation only therapy (n=80). SEGT did not improve survival (median survival 24 mths in SEGT vs 18.3 in controls; univariate HR for death=0.92, 95% CI, 0.69 to 1.26. However, SEGT ameliorated and prevented new DSM-IV depressive disorders (p=0.002), reduced hopeless-helplessness (p=0.004), trauma symptoms (p=0.004) and improved social functioning.116, level I

Two hundred and twenty seven women who were surgically treated for regional breast cancer and waited for adjuvant therapy were recruited in a RCT. These women were assigned to either a psychological intervention (i.e. small patient groups which included strategies to reduce stress improve mood, alter health behaviours, and maintain adherence to cancer treatment and care) or no intervention. Results showed that total mood disturbance significantly decreased more in the intervention arm for patients with high initial cancer stress (F=4.13, p < 0.05) and similarly for anxiety (F=4.15, p < 0.05) and fatigue (F=5.14, p < 0.05). The patients in intervention arm also improved in overall dietary habits (F=5.01, p < 0.05) and decreased their smoking behaviour (F=4.52, p < 0.05). Results also showed significant improvement in immune responses in the intervention group (p < 0.05).117, level I

40

A quasi experimental study was conducted to assess the effectiveness of hospital support

group. In this study, 94 who attended the support group were compared to those who

declined (n=71). Results showed a significant difference in anxiety and depression

between the groups (p < 0.001) and that participants in intervention group continued to

have less anxiety at 12 months (OR=2.5, CI 95% 1.56. to 5.51).118, level II-1

A SR (n=13 RCTs) looked at the effects of psychosocial interventions on the quality of

life of patients with advanced breast cancer. All trials used a randomisation procedure to

allocate the psychosocial intervention. Out of 13 trials, 12 showed positive effects on one

or more indicators of quality of life (QoL).119, level I

Arving et al. conducted a RCT comparing the effectiveness of psychosocial support

provided by oncology nurses specially trained in psychological techniques, individual

psychologists and standard care on quality of life, emotional well-being and life events

among breast cancer patients. Consecutive patients with breast cancer (n=425) were

considered. A total of 179 (62%) patients were randomised in blocks of nine into one

of three groups and assessed at baseline: (a) individual nurse support [INS] (n=60), (b)

Individual Psychosocial support [IPS] (n=60) or (c) standard care [SC] (n=59). Results

showed the following: at 6 months follow up, systemic therapy side effects increased

significantly in the IPS and SC groups but not the INS group (p < 0.001); more patients

in the INS and IPS groups improved clinically significantly from in anxiety (p < 0.01),

depression (p < o.05) and in intrusion thoughts (p < 0.001). It was concluded that

psychosocial support using techniques derived from cognitive behavioural therapy, such

as relaxation and distraction, activity scheduling and ways to improve communication,

was beneficial for breast cancer patients and that psychosocial support can be provided

both by specially trained oncology nurses and psychologists.120, level I

RECOMMENDATION

Psychosocial support should be provided by trained personnel for women with breast cancer, particularly to those with high initial emotional distress. (Grade A)

8.4 Breast Care Nurse (BCN)

The role of a BCN is to provide treatment and management information and psychosocial support from the time of diagnosis and throughout women’s treatment journey.

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NICE guidelines suggested that adding the services of an advanced practice care nurse to standard care significantly reduced uncertainty, complexity, inconsistency and unpredictability without influencing quality of life or mood. Support from a BCN following cancer surgery alleviated depression over time but made no significant difference to anxiety. However, receiving support from the breast care nurse specialist before and after receiving a pre-surgical diagnosis significantly lowered clinically-relevant anxiety when measured two weeks after surgery regardless of eventual diagnosis. Evidence also showed that psycho-educational intervention, delivered by a BCN to women with breast cancer after primary treatment was effective thus providing a ‘safe passage’ from treatment to survivorship.54

New Zealand guidelines and the SIGN guidelines recommended that the role of a BCN was vital within the treatment team as it resulted in a reduction in psychological morbidity, improved the continuity of care, information and support for women from diagnosis to follow up and was useful to identify anxiety and depression.61,109

SIGN guidelines and Belgian guidelines stated that using a structured approach to psychological care allowed breast care nurse specialists to improve the continuity of care information and support the women receive from the time of diagnosis until follow up. All women with potential or known diagnosis of breast cancer should have access to a breast care nurse specialist for information and support at every stage of diagnosis and treatment. The BCN should have appropriate education and experience.55,109

An observational study that used a mixed method design with a random sampling (n=51) stated that BCN played an important role in providing relevant and necessary information and offered great support to women with breast cancer and thus improved patient outcomes.121, level III Another survey (n=544) found that women who received care from the breast cancer nurse were better informed (p = 0.001) and felt better supported compared to who had no breast nurse contact.122, level III

In another a retrospective survey by Scwajeer et al. (n = 50), women (93%) benefited from the BCN’s intervention in general. Members of the multi-disciplinary team also confirmed the functions of BCN role. They identified the BCN contribution to the continuity of women’s care as a major strength especially on the role for psychosocial support and information, a source of expert advice and were found to be helpful in the women’s recovery.123, level III

RECOMMENDATION

All patients with breast cancer should be assigned to a breast care nurse who will support them throughout the diagnosis, treatment and follow up. (Grade A)

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8.5 Psycho-education Programmes

Women with breast cancer experience anxiety related to their diagnosis and side-effects of cancer treatment. They need knowledge to cope with their diagnosis of breast cancer. Those who obtain up-to-date information on breast cancer treatments and management have an increased awareness of choices available to manage the disease and gain a sense of control. SIGN guidelines recommended that women with breast cancer should be offered audiotapes or follow up summary letters of important consultations.109

Santon et al. assessed the effectiveness of psycho-educational programme in improving physical and emotional well-being among women newly diagnosed with stage I or II breast cancer. The programme consisted of multiple sources of information such as standard printed material (CTL) vs CTL and also peer modelling videotape (VD) vs CTL, VD, psycho-educational counselling and informational workbook (EDU). Findings suggested that a peer-modeling videotape (VD) could accelerate the recovery of energy during the re-entryphaseinwomentreatedforbreastcancer.Apeer–modellingtape(VD)tobeusedwith other psycho-educational programmes on is recommended for women upon their diagnosis of breast cancer.124, level I

Effect of the breast cancer educational Intervention (BCEI) studies on overall QoL was studied in 256 women with breast cancer within one year of diagnosis. The educational programme consisted of face to face education (thrice in six months), emotional support via telephone (thrice in six months), follow up education, and support and telephone discussions, written materials and audiotapes. It was found that BCEI was effective in enhancing QOL of women diagnosed with breast cancer.125, level I

Yates et al. evaluated the efficacy of a psycho-educational intervention in improving cancer- related fatigue for early stage breast cancer on 109 women using a RCT design. Preparatory education and support had the potential to assist women to cope with cancer-related fatigue.126, level I

The effect of a supportive care programme on anxiety level of women with suspected breast cancer during the diagnostic period was conducted using a longitudinal, quasi-experimental design. Findings suggested that a supportive care programme that incorporates informational and emotional support and follow up telephone consultations can decrease anxiety levels of women with suspected breast cancer.127, level II-1

Wolf used a focus group interview to explore experiences of women after undergoing breast reconstruction on how their information need could be met. A small sample (eight women) who were randomly selected wanted their decision-making to be guided by surgeon and recommended that the sources of information found to be relevant and helpful which included the surgeon, breast care nurse, photographs, and contact with other patients, written information, a tape of consultation and information videotapes.128, level III

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One RCT by William and Schreier determined the effectiveness of informational audiotapes on self-care behaviours, state of anxiety and use of self-care behaviours. Findings suggested that informational audiotapes were effective teaching tools and can be an effective means for providing instructions about self-care behaviours and lowering anxiety.129, level I

Another RCT evaluated the usefulness of an educational video with regards to the patient’s ability to recall and report side-effects of chemotherapy. All participants (n=30) in the intervention group were satisfied with the video and the video group had a higher recall of information (66.7%) compared to those (10%) who preferred discussion with nurse and written information. Findings suggested that the inclusion of a video in chemo education improved retention of information regarding chemo side effects.130, level I

Wilmoth et al. did a RCT to describe women’s perceptions of the effectiveness of telephone support and educational materials on their adjustment to breast cancer. Participants who received telephone support for one year, in addition to educational materials, reported improvement in their attitudes toward their breast cancer and better relationships with their spouses compared to 38% in the control group.131, level I

RECOMMENDATION

Psycho-education programmes such as printed materials (given face to face/taken home), audiotape, peer modelling video tapes, telephone support and/or counselling should be provided for all women upon their diagnosis of breast cancer. (Grade A)

8.6 Palliative Care

Palliative care aims to maximise the quality of life in the time remaining for the patient with breast cancer.

Palliative care is an approach that improves the QoL of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems physical, psychosocial or spiritual in nature. Palliative care:• provides relief from pain and other distressing symptoms• affirms life and regards dying as a normal process• intends neither to hasten or postpone death• integrates the psychological and spiritual aspects of patient care• offers a support system to help patients live as actively as possible until death• offers a support system to help the family cope during the patients’ illness and in

their own bereavement

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• uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated

• will enhance quality of life, and may also positively influence the course of illness

• is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications

Source: WHO Definition of Palliative Care (internet communication 17 Feb 2010) at http://www. who.int/cancer/palliative/definition/en/

A SR was carried out to look at the effectiveness of palliative care or hospice care team. In this review, a meta-regression of 26 studies found slight positive effect (0.1), of palliative and hospice care team (PCHCT) on patient outcomes, independent of team make-up, patient diagnosis, country, or study design. On the other hand, a meta-analysis of 19 studies demonstrated small benefit on patients’ pain (OR=0.38, 95% CI 0.23 to 0.64) and other symptoms (OR=0.51, 95% CI 0.30 to 0.88) but a non-significant trend towards benefits for satisfaction and therapeutic interventions. Data regarding home deaths were equivocal. While the meta-synthesis of all studies found wide variations in the type of service delivered by each team, there was no discernible difference in outcomes between city, urban, and rural areas. Evidence of benefit was strongest for home care.132, level I

A RCT of 322 patients with advanced cancer found that nurse-led palliative psycho-educational intervention improved quality of life and mood but no differences was seen in symptom intensity. 133, level I

A multicentre RCT (n= 517) found that inpatient palliative care services improved satisfaction on care (p = 0.04) and communication (p = 0.004), reduced Intensive Care Unit admission (p = 0.04) and lower 6-month net cost savings of $4,855 per patient (p = 0.001) but there was no difference in symptom control and survival. There are several possible explanations for the effect of palliative care team on symptom control. First, patients in this study reported relatively low physical symptoms at study enrolment. The mean pain rating on a scale of 1 to 10 was 3.4 suggesting that pain was less than in other reported populations whose symptoms were more severe. Second, the average index hospitalisation length of stay after study enrolment was 4.9 days, a shorter time for the palliative care team to manage complex physical symptoms compared to studies with longer interventions. Finally, this patient population survived for a longer period of time indicating they might be earlier in their disease state than other inpatient palliative care patients.134, level I

RECOMMENDATIONThe palliative care physician should be involved in management of advanced breast cancer. (Grade A)

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9. FOLLOW UP

With regard to follow up schedule after treatment of breast cancer, NICE technology review 2002 advised that patients should be followed up in a hospital setting for a minimum of three years.135, level III The most recent guidelines did not mention the follow up period. It was concluded that the available studies were unable to indicate an ideal frequency of follow up. However, annual mammography and regular physical examination were recommended.54

Even though studies showed that mammography (MMG) had high sensitivity and specificity in detecting recurrent ipsilateral breast cancer and contra-lateral new cancer, but SR of observational studies concluded that routine follow up MMG did not directly improve survival in patients treated for breast cancer. In contrast, a separate meta-analysis concluded that detection of loco-regional or contra-lateral recurrence in asymptomatic patients during follow up or assessed by mammography improved survival compared to late symptomatic detection.61

Minimal requirement for regular follow-up of a primary breast cancer is a clinical review every three months for the first year, then six-monthly for five years, then an annual review thereafter.136

During follow up, history and physical examination should be carried out. Blood tests and diagnostic imaging have not been found to improve survival or quality of life more than does physical examination for detecting distant metastasis. The patient is also advised to carry out monthly breast self-examination.137

RECOMMENDATION

Regular follow up should be scheduled as follows:

• three monthly for the first year

• then six-monthly for five years

• then an annual review thereafter (Grade C)

Annual mammography should be offered to all patients with early breast cancer who has undergone treatment to detect recurrence or contra-lateral new breast cancer. (Grade C)

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10. LIFESTYLE MODIFICATION IN BREAST CANCER SURVIVORS

In the Women’s Intervention Nutrition Study (n=2,437), the effect of fat reduction intake in women with resected, early stage breast cancer receiving conventional cancer management was studied. Dietary fat intake at 12 months was significantly lower (p < 0.001) in the intervention group with intake of 33.3 g/day (95% CI 32.2 to 34.5) vs 51.3 (95% CI 50.0 to 52.7) in the control group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) had been reported (9.8% of the intervention versus 12.4% of control group). The HR of relapse events was 0.76 in favour of the intervention group (95% CI 0.60 to 0.98). The author concluded that a lifestyle intervention of reducing dietary fat intake, with modest influence on body weight, may improve relapse free survival of breast cancer patients.55

The Women’s Healthy Eating and Living (WHEL) RCT (n=3109) examined whether an increase in vegetable, fruit and fiber intake and a decrease in dietary fat intake reduced the risk of recurrent and new primary breast cancer and all causes mortality in women with previously treated early stage breast cancer. Over the mean 7.3-year follow-up, 16.7% women in the intervention group versus 16.9% in the comparison group experienced an invasive breast cancer event (adjusted HR=0.96; 95% CI 0.80 to 1.14). On the other hand, 10.1% in intervention group vs 10.3% in the control group died (adjusted HR=0.91, 95% CI 0.72 to 1.15). The DFS curves were virtually identical across groups. The study concluded that the adoption of a diet that was very high in vegetables, fruit and fiber, and low in fat did not reduce additional breast cancer events or mortality.138, level I

In a cohort study (n=3,846) examining whether high intake of animal fat was associated with increased breast cancer mortality and high intake of fibre was associated with decreased breast cancer mortality showed that in simple models adjusted for time since diagnosis, age, and energy intake, animal fat intake was associated with increased breast cancer death, while cereal fibre intake was associated with reduced breast cancer death. However, no association were found in fully adjusted models: the RR for increasing quintiles for animal fat was 1.00, 0.89, 0.86, 0.85, and 0.89 (95% Cl 0.61 to1.28) while for cereal fibre, they were 1.00, 0.95, 0.76, 0.81, and 1.00 (95% Cl 0.71 to 1.40). Results of simple models adjusted for physical activity were similar to those for full multivariate models. They showed that physical activity decreased the risk of death from breast cancer (p < 0.001).139, level II-2

RECOMMENDATION

Diet high in fibre and low in fat together with physical activity should be advised in women with breast cancer. (Grade B)

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11. FAMILIAL BREAST CANCER

11.1 Genetic Counselling for Inherited Risk to Hereditary Breast and Ovarian Cancer

There are no population-based RCTs of risk assessment and genetic testing using the outcomes of incidence of breast and ovarian cancer or cause-specific mortality.

The USPSTF found good evidence that genetic counselling and genetic testing services improved important health outcomes and concluded that benefits substantially outweigh harms.140

Frank et al. examined the results for BRCA1 and BRCA2 genetic testing of > 10,000 women in USA and found that specific features of personal and family history could be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting. 141, level III This is supported by Mann et al. who examined the results of BRCA1 and BRCA2 genetic testing of 822 families in Australia and found similar features could be used to assess the likelihood of identifying mutation carriers.142, level III

Thirthagiri et al. examined the results of BRCA1 and BRCA2 genetic testing of 187 individuals in Malaysia and found similar features can be used to assess the likelihood of mutation carriers in Asians but reported that existing risk prediction models underestimated the number of carriers in Asian cohorts.143, level III

As a result of the medical, legal and ethical implications of genetic testing, all genetic testing should be accompanied by appropriate pre- and post-genetic counselling which should be provided by suitably trained personnel.

There is currently no evidence to support the use of genetic testing of other genes or genetic loci in routine clinical practice.

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RECOMMENDATION

Women whose family history is associated with an increased risk for deleterious

mutations in BRCA1, BRCA2 or TP53 genes should be referred for genetic counselling

and evaluation for genetic testing. This includes individuals with affected blood

relatives with any one of the following family history patterns (These individuals should

be from the same side of family):

• 2 or more first or second degree relatives on the same side of family with breast

or ovarian cancer any age; or

• 2 or more first or second degree relatives on the same side of family with breast

cancer, 1 of whom was diagnosed ≤ age 50 years old; or

• 1 first degree relative with breast cancer diagnosed ≤ age 40 years old; or

• 1 first degree relative with both breast and ovarian cancer at any age; or

• 1 first degree relative with bilateral breast cancer at any age; or

• 1 first degree relative with male breast cancer; or

• 2 or more first or second degree relatives on the same side of family with

ovarian cancer at any age; or

• Family history of breast cancer in combination with other BRCA-related

cancers, such as pancreas, prostate and oesophageal cancers on the same

side of family; or

• Family history of early onset breast cancer in combination with other TP53-

related cancers such as sarcomas and multiple cases of childhood cancers on

the same of family. (Grade C)

Genetic counselling or routine breast cancer susceptibility gene testing for women

whose personal or family history is not associated with an increased risk for deleterious

genetic mutations should not be offered. (Grade C)

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11.2 Interventions which Reduce the Incidence and Mortality of Breast and Ovarian Cancer in Women Identified as High Risk by Personal or Family History, Positive Genetic Test Results or Both

There is strong evidence that individuals with significant family history or pathogenic mutations in BRCA1 or BRCA2 have a significantly higher risk of breast and other related cancers.144, level II-3; 145, level II-2

Individuals with significant family history (see family history criteria in the recommendation 11.1) but with no pathogenic mutations in BRCA1 and BRCA2 remain high risk to familial breast and ovarian cancer and should therefore be offered appropriate counselling and clinical management based on their age and family history.146, level III

For individuals with pathogenic BRCA1 and BRCA2 mutations, have an inherited risk of breast, ovarian and a number of related cancers. For BRCA1 mutation carriers, the estimated lifetime risk of breast cancer ranges from 40% to 85%, and the estimated lifetime risk of ovarian cancer ranges from 20% to 65%.144, level II-3; 145, level II-2 For BRCA2 mutation carriers, the breast cancer risk is similar, but the lifetime risk of ovarian cancer is approximately 20%.144, level II-3; 145, level II-2 BRCA1 or BRCA2 mutation carriers also have a higher incidence of contralateral breast cancer within the first five years of follow up after the primary breast cancer i.e. 12 - 33% among BRCA1 or BRCA2 mutation carriers or (2.4 - 6.5% per year)147, level II-3; 148, II-3; 149, level II-3; 150, level II-3; 151, level II-3; 152, level II-3, 153, level II-3 as compared to a 0.4 - 1% per year for breast cancer patients in general.154, level II-3

11.3 Intensive Screening

11.3.1 Breast Cancer

Intensive screening for breast cancer in BRCA mutation carriers is recommended by expert groups155, level III, but there is currently no trial of the effectiveness of intensive screening in reducing mortality. MRI is more sensitive for detecting breast cancers (sensitivity of 77%) than mammography (sensitivity of 36%), ultrasound (sensitivity of 33%) or clinical breast examination alone (sensitivity of 9%).156, level I; 157, level I

11.3.2 Ovarian Cancer

Early ovarian cancer is asymptomatic and the available techniques have not been demonstrated to be effective for early diagnosis. Intensive screening for ovarian cancer in BRCA carriers is therefore not supported because of the current limitations in sensitivity and specificity of transvaginal ultrasounds and/or measurement of serum CA125 level. 157, level II-3; 158, level II-3 Risk reducing salpingo-oophorectomy (RRSO) is therefore strongly recommended to BRCA1/2 mutation carriers once childbearing is complete.

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11.4. Chemoprevention

11.4.1 Tamoxifen, Raloxifene and Anastrazole

A number of large chemoprevention trials159, level I;160, level I;161, level I; 162, level I had shown that tamoxifen and raloxifene significantly reduced the overall risk of breast cancer, but this effect was observed only for oestrogen receptor-positive but not oestrogen receptor-negative tumours. Although the numbers are small, the data also suggested that tamoxifen may reduce the risk for breast cancer for BRCA2 carriers but not for BRCA1 carriers,163, level II-3 and may also reduce the risk of contralateral breast cancer in BRCA carriers.164, level II-3 Notably, there is no data on overall mortality benefit and use of tamoxifen associated with several adverse effects, including increased in thromboembolic events, stroke, endometrial cancer and gynaecological problems. 162, level I

There is currently an ongoing large randomised trial addressing the efficacy of anastrazole in the prevention of breast cancer.165, level I

11.4.2 Oral Contraceptives

No RCT of oral contraceptives to prevent breast or ovarian cancer have been published. Although observational studies indicate that oral contraceptives are associated with reduced ovarian cancer in the general population and in BRCA1 and BRCA2 mutation carriers, it may not be associated with an increased risk of breast cancer.166, level II-2; 167, level

II-2; 168, level II-2

11.4.3 Prophylactic Surgery

No RCT of prophylactic surgery have been conducted as this would not be ethical and therefore, conclusions can only be drawn from cohort studies which have intrinsic bias’ that may lead to over- and/or under-estimation of effects.140, level II-2

11.4.4 Bilateral Prophylactic Mastectomy

All studies of prophylactic bilateral mastectomy in high risk women are consistent and indicate an 85 - 100% reduction in risk to breast cancer169, level II-2;148, level II-2;170, level II-2;

171, level II-2; 140, level II-2; 150, level II-2 but there is insufficient evidence that bilateral prophylactic mastectomy (BPM) leads to improved survival. A small number of cohort studies had examined the possible harms associated with BPM and reported that the majority of women were satisfied with the procedure when combined with reconstructive surgery and reported of diminished concerns about breast cancer after BPM.172, level II-2; 173, level II-2 Notably, a number of studies have reported the presence of occult tumours in up to 4% of at-risk breasts at the time of prophylactic surgery,169, level II- 2; 174, level II-2 highlighting the need for careful pathological assessment at the time of surgery.

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11.4.5 Contralateral Prophylactic Mastectomy

Whilst some studies have shown that BRCA carriers may have an increased risk of

ipsilateral breast cancer, this has not been found in other studies. However, the majority of

studies of consistently show that BRCA carriers have a higher risk of contralateral breast

cancer compared to non-BRCA carriers.147, level II-2; 148, level II-2; 149, level II-2; 150, level II-2; 151, II-2; 152, level

II-2; 153, level II-2 Moreover, the majority of studies of prophylactic contralateral mastectomy in

high-risk women are also consistent, indicating an 85 - 100% reduction in risk to breast

cancer and increased overall survival.147, II-2; 148, II-2; 150, II-2 A small number of cohort studies

have examined the possible harms associated with contralateral prophylactic mastectomy

(CPM) and reported that the majority of women are satisfied with the procedure and

reported of diminished concerns about breast cancer after CPM.175, II-2

11.4.6 Bilateral Salpingo-oophorectomy

Risk reducing salpingo-oopherectomy (RRSO) remains the most effective risk reduction

strategy for the prevention of BRCA1- and BRCA2-associated gynecological cancers.

RRSO can lead to reduced risk for ovarian cancer of 85 - 100% and breast cancer of 53

- 68%.176, level II-2; 177, level II-2; 144, level II-2; 178, level II-2 and at least in one study, bilateral prophylactic

salpingo-oophorectomy (BPSO) was associated with an improvement in overall survival.179,

level II-2 Notably, a number of studies have shown that occult cancers occur in up to 6.3%

of ovaries and fallopian tubes, and it is therefore recommended that extensive pathologic

evaluation is conducted on resected ovaries and fallopian tubes, even when they appear

macroscopically normal.180, level II-2; 181, level II-2; 144, level II-2; 182, level II-2; 183, level II-2 Pre-menopausal

high risk women are the most likely to benefit from prophylactic oophorectomy, but also

the most likely to experience side effects from surgery, including the loss of fertility,

loss of sexual function and increased osteoporosis,184, level II-2 and therefore prophylactic

oophorectomy is advised after completion of childbearing and from the age of 40 years old.

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RECOMMENDATION

Appropriate counselling and clinical management should be offered to individual with

significant family history but with no pathogenic mutation in BRCA1 and BRCA2 as

they remain at high risk to familial breast and ovarian cancer. (Grade B)

Screening women with high risk for breast cancer should be done from age of 30

years with both MRI and mammography as it is more effective than mammography

alone (Grade B)

Risk reducing salpingo-oophorectomy should be offered to BRCA1/BRCA2 mutation

carriers once childbearing is complete. (Grade B)

Bilateral prophylactic mastectomy should be offered to women with deleterious

mutations in BRCA1/BRCA2. (Grade B)

Contralateral prophylactic mastectomy may be offered to women with breast cancer

who have deleterious mutations in BRCA1/ BRCA2. (Grade B)

Individuals with deleterious mutations in BRCA1/BRCA2 should be managed by a

multidisciplinary team. (Grade C)

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REFERENCESREFERENCES

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167. Brohet RM, Goldgar DE, Easton DF, et al. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol. 2007;25(25):3831 - 6.

168. McLaughlin JR, Risch HA, Lubinski J, et al.,. Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol. 2007;8(1):26 - 34.

169. Evans D, Baildam A, Anderson E, et al. Risk reducing mastectomy: outcomes in 10 European centres. J Med Genet 2009;46(4):254 - 8.

170. Bermejo-Perez MJ, Marquez-Calderon S, and Llanos-Mendez A. Effectiveness of preventive interventions in BRCA1/2 gene mutation carriers: a systematic review. Int J Cancer. 2007;121(2):225 - 31.

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171. Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, et al. Prophylactic mastectomy in BRCA1/2 mutation carriers and women at risk of hereditary breast cancer: long-term experiences at the Rotterdam Family Cancer Clinic. Ann Surg Oncol. 2007;14(12):3335 - 44.

172. Brandberg Y, Sandelin K, Erikson S, et al. Psychological reactions, quality of life, and body image after bilateral prophylactic mastectomy in women at high risk for breast cancer: a prospective 1-year follow-up study. J Clin Oncol. 2008;26(24):3943 - 9.

173. Tercyak KP, Peshkin BN, Brogan BM, et al. Quality of life after contralateral prophylactic mastectomy in newly diagnosed high-risk breast cancer patients who underwent BRCA1/2 gene testing. J Clin Oncol 2007;25(3):285 - 91.

174. Kroiss R, Winkler V, Kalteis K, Bikas D, Rudas M, Tea M, et al. Prevalence of pre-malignant and malignant lesions in prophylactic mastectomy specimens of BRCA1 mutation carriers: comparison with a control group. J Cancer Res Clin Oncol. 2008 Oct;134(10):1113-21.

175. Frost MH, Slezak JM, Tran NV, et al. Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance. J Clin Oncol. 2005;23(31):7849 - 56.

176. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009 Jan 21;101(2):80-7.

177. Kauff N, Domchek S, Friebel T, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26(8):1331 - 7.

178. Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol. 2005 Oct 20;23(30):7491-6.

179. Domchek SM, Friebel TM, Neuhausen SL, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Lancet Oncol. 2006;7(3):223 - 9.

180. Rabban JT, Barnes M, Chen LM, et al. Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma. Am J Surg Pathol 2009;33(8):1125 - 36.

181. Callahan MJ, Crum CP, Medeiros F, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol. 2007;25(25):3985 - 90.

182. Hermsen BB, van Diest PJ, Berkhof J, et al. Low prevalence of (pre) malignant lesions in the breast and high prevalence in the ovary and Fallopian tube in women at hereditary high risk of breast and ovarian cancer. Int J Cancer. 2006;119(6):1412 - 8.

183. Powell CB, Kenley E, Chen LM, et al. Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol. 2005;23(1):127 - 32.

184. Madalinska JB, Hollenstein J, Bleiker E, et al. Quality-of-life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol. 2005;23(28):6890 - 8.

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APPENDIxESAPPENDIxES

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APPENDIX 1

SEARCH TERMS

The following free text word or MeSH terms were used either singly or in combination:alcohol and breast cancer, age AND risk of breast cancer, radiation AND breast cancer, reproductive risk AND breast cancer, hormonal exposure AND breast cancer, obesity AND breast cancer, referral to breast clinic, benign breast disease AND breast cancer risk, benign breast disease AND breast cancer risk, physical activity AND breast cancer, effective method for breast cancer screening among population, “breast self examination” AND “breast cancer screening”, “Clinical breast examination” AND “breast cancer screening”, breast screening - high risk women MRI, magnetic resonance imaging AND Invasive lobular carcinoma, magnetic resonance imaging in atypical hyperplasia AND invasive lobular carcinoma, breast cancer AND ultrasound AND mammography, breast cancer OR breast disease AND diagnosis, breast cancer AND triple assessment, preoperative MRI AND breast cancer, PET CT AND “breast cancer” AND staging, PET CT AND “breast cancer” AND role, PET CT AND “breast cancer” AND diagnosis, “breast cancer” AND scintigraphy, PET AND PET/CT AND “breast cancer”, PET CT, breast cancer, staging breast cancer, “metastatic breast cancer” AND Imaging, breast cancer and staging and CT thorax, breast cancer , staging, staging breast cancer, imaging breast cancer, staging AND “breast cancer”, “breast neoplasm” OR “breast carcinoma” OR “breast cancer” AND “fine needle aspiration cytology” AND “core needle biopsy” OR “core biopsy” OR “needle biopsy” AND accuracy, FISH AND CISH, “breast carcinoma” OR “breast cancer” AND “minimum dataset” OR “synoptic report” OR “proforma report” , surgical treatment for early breast cancer, contraindications to breast conservative surgery, breast conserving surgery vs mastectomy, mastectomy vs breast conserving surgery, centrally located breast cancer, breast conserving surgery AND centrally located breast cancer, tumour free margin for breast cancer, sentinel node biopsy AND DCIS, sentinel node biopsy AND DCIS, timing of breast reconstruction, locally advanced breast cancer AND neo-adjuvant chemotherapy, locally advanced breast cancer AND neo-adjuvant chemotherapy, locally advanced breast cancer AND neo-adjuvant therapy, neo-adjuvant chemotherapy response AND breast cancer, surgery in metastatic breast cancer, Hepatic resection, liver metastases, breast cancer, breast neoplasms AND trastuzumab OR lapatinib, -breast neoplasms AND tamoxifen OR aromatase inhibitors, breast neoplasms AND goserelin, breast neoplasms AND tamoxifen OR aromatase inhibitors, radiotherapy, breast neoplasms, radiotherapy, breast neoplasms, “hospital anxiety AND depression scale” AND “breast cancer”, CBT AND “breast cancer”, “behavioral therapy” OR “cognitive therapy” AND “breast cancer”, “psychological assessment” AND “breast cancer”, distress AND assessment AND “breast cancer”, BDI AND “breast cancer”, Valid measures AND “breast cancer”, psycho-education intervention And breast cancer, psycho-education materials AND breast cancer, information materials and breast cancer, breast cancer nurse, breast care nurse, breast cancer nurse specialist, breast cancer nurse, palliative care AND quality of life, follow-up schedule for breast cancer, lifestyle modification increase survival rate for breast cancer survivors, “lifestyle modification” AND “survival rate for breast cancer patients”, “lifestyle modification” and “increase survival rate”, women’s healthy eating and living study, “dietary fat reduction” AND “breast cancer outcome”

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APPENDIX 2

CLINICAL QUESTIONS

Risk factor• What are the risk factors of breast cancer?

Screening• What is the most effective method of screening breast cancer among the

general population?• What is the most effective method of screening for breast cancer among the

high risk group?

Referred• What are the criteria for referral to breast clinic?

Radiology• What is the diagnostic accuracy of ultrasound and mammography together

compared with ultrasound or mammography alone in detecting breast cancer?• What is the role of triple assessment in the diagnosis of breast cancer?• What is the role of magnetic resonance imaging of the breast in the pre-

operative assessment of patients with biopsy-proven DCIS or invasive breast cancer?

• What is the role of PET or PET/CT in patients with breast cancer?• What is the recommended imaging modality to investigate the extension of the

disease in patients with breast cancer?

Pathology• In the diagnosis of breast cancer, is FNAC as accurate as core biopsy?• What is the best method to test for HER-2 over expression in patients with

breast cancer?• What are the elements of an adequate pathology report for breast cancer?

Surgical Management• What is the appropriate surgical management for women with early breast

cancer?• What are the contraindications to breast conserving surgery (BCS)? Is BCS

amenable for centrally located tumour?• What is the adequate tumour free margin in breast conserving surgery?• What is the role of axillary surgery in early breast cancer? What are the

indications for sentinel lymph node biopsy in breast cancer?

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• Does the timing of breast reconstructive surgery alter the local recurrence rate and overall survival?

• What is the role of neoadjuvant chemotherapy in locally advanced breast cancer? Which subgroup will response better with neoadjuvant chemotherapy?

• What is the role of surgery for the primary tumour in metastatic breast cancer?• Does removal of metastatic disease improve overall survival?

Oncology• What are the indications and benefits of taxane-based regimens versus

anthracycline- based regimens in early breast cancer?

• What are the indications and survival benefits for anti-HER-2 treatment in early or locally advanced breast cancer?

• In patients with early invasive breast cancer and DCIS, what is the effectiveness of endocrine therapy?

• In pre-menopausal breast cancer patients, what is the role of ovarian suppression or ovarian ablation?

• In post-menopausal breast cancer patients, what are the benefits of aromatase inhibitors versus tamoxifen in the adjuvant, neo-adjuvant and advanced setting?

• In patients who had mastectomy, does radiotherapy to the chest wall reduce the risk of local recurrence and improve overall survival?

• In patients who have had BCS, does radiotherapy to the breast reduce the risk of local recurrence and improve overall survival?

Psychology Support• What assessments have been shown to be useful in identifying emotional and

mental health status of women diagnosed with breast cancer?• Is cognitive behaviour therapy (CBT) effective in improving emotional well-being

and quality of life among women diagnosed with breast cancer?• How effective is psychosocial support (such as supportive group therapy) and

psycho-education materials in improving the well being and quality of life of women with breast cancer and their families, and to cope with their disease?

• How effective are psychoeducation materials in assisting breast cancer patients to cope with their diagnosed breast cancer?

• What is the role of breast cancer nurse specialist?• What is the effect of palliative care compared to standard care in quality of life

of cancer patients?

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Follow Up• What is the follow up schedule and procedures after treatment of breast

cancer?• Does lifestyle modification increase survival rate of breast cancer survivors?

Familial Breast Cancer• Who should be offered genetic counselling for inherited risk to hereditary

breast and ovarian cancer?• Management of risk i.e. mastectomy, surveillance and chemoprevention

in three groups of women: (a) affected BRCA carriers, (b) unaffected BRCA carriers and (c) high risk but no mutations in BRCA1 and BRCA2?

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APPENDIX 3

AJCC STAGING (TNM CLASSIFICATION) 7TH EDITION

Primary Tumour (T)The T classification of the primary tumour is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimetre. If the tumour size is slightly less than or greater than a cut-off for a given T classification, it is recommended that the size be rounded to the millimetre reading that is closest to the cut-off. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript “c” or “p” modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements respectively. In general, pathologic determination should take precedence over clinical determination of T size.

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

Tis (DCIS) Ductal carcinoma in situ

Tis (LCIS) Lobular carcinoma in situ

Tis (Paget’s)

Paget’s disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget’s disease are categorised based on the size and characteristics of the parenchymal disease, although the presence of Paget’s disease should still be noted.

T1 Tumour ≤ 20 mm in greatest dimension

T1mi Tumour ≤ 1 mm in greatest dimension

T1a Tumour > 1 mm but ≤ 5 mm in greatest dimension

T1b Tumour > 5 mm but ≤ 10 mm in greatest dimension

T1c Tumour > 10 mm but ≤ 20 mm in greatest dimension

T2 Tumour > 20 mm but ≤ 50 mm in greatest dimension

T3 Tumour > 50 mm in greatest dimension

T4Tumour of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)

Note: Invasion of the dermis alone does not qualify as T4

T4aExtension to the chest wall, not including only pectoralis muscle adherence/invasion

T4bUlceration and/or ipsilateral satellite nodules and/or oedema (including peaud’orange) of the skin, which do not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b

T4d Inflammatory carcinoma (see “Rules for Classification”)

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Regional Lymph Nodes (N)

Clinical

NX Regional lymph nodes cannot be assessed (e.g. previously removed)

N0 No regional lymph node metastases

N1 Metastases to movable ipsilateral level I, II axillary lymph node(s)

N2

Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or

matted; or in clinically detected * ipsilateral internal mammary nodes in the absence

of clinically evident axillary lymph node metastases

N2aMetastases in ipsilateral level I, II axillary lymph nodes fixed to one

another (matted) or to other structures

N2b

Metastases only in clinically detected * ipsilateral internal mammary

nodes and in the absence of clinically evident level I, II axillary lymph

node metastases

N3

Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or

without level I, II axillary lymph node involvement; or in clinically detected * ipsilateral

internal mammary lymph node(s) with clinically evident level I, II axillary lymph node

metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without

axillary or internal mammary lymph node involvement

N3a Metastases in ipsilateral infraclavicular lymph node(s)

N3bMetastases in ipsilateral internal mammary lymph node(s) and axillary

lymph node(s)

N3c Metastases in ipsilateral supraclavicular lymph node(s)

* Note: Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by

clinical examination and having characteristics highly suspicious for malignancy or a presumed

pathologic macrometastasis based on fine needle

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Pathologic (pN)*

pNXRegional lymph nodes cannot be assessed (e.g. previously removed, or not removed for pathologic study)

pN0 No regional lymph node metastasis identified histologically

Note: Isolated tumour cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumour cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.

pN0(i−) No regional lymph node metastases histologically, negative IHC

pN0(i+)Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC)

pN0(mol−)No regional lymph node metastases histologically, negative molecular findings RT-PCR)

pN0 (mol+)Positive molecular findings (RT-PCR), ** but no regional lymph node metastases detected by histology or IHC

pN1Micrometastases; or metastases in 1 - 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected ***

pN1miMicrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm)

pN1aMetastases in 1 - 3 axillary lymph nodes, at least one metastasis greater than 2.0 mm

pN1bMetastases in internal mammary nodes with micro-metastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected ***

pN1cMetastases in 1 - 3 axillary lymph nodes and in internal mammary lymph nodes with micro-metastases or macro-metastases detected by sentinel lymph node biopsy but not clinically detected

pN2Metastases in 4 - 9 axillary lymph nodes; or in clinically detected **** internal mammary lymph nodes in the absence of axillary lymph node metastases

pN2aMetastases in 4 - 9 axillary lymph nodes (at least one tumour deposit greater than 2.0 mm)

pN2bMetastases in clinically detected **** internal mammary lymph nodes in the absence of axillary lymph node metastases

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pN3

Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected **** ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micro-metastases or macro-metastases detected by sentinel lymph node biopsy but not clinically detected *** ; or in ipsilateral supraclavicular lymph nodes

pN3aMetastases in ten or more axillary lymph nodes (at least one tumour deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes

pN3b

Metastases in clinically detected **** ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micro-metastases or macro-metastases detected by sentinel lymph node biopsy but not clinically detected ***

pN3c Metastases in ipsilateral supraclavicular lymph nodes

Notes: * Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for “sentinel node,” for example, pN0(sn)

** RT-PCR: reverse transcriptase/polymerase chain reaction

*** “Not clinically detected” is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination

**** “Clinically detected” is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macro-metastasis based on fine needle aspiration biopsy with cytologic examination

Distant Metastases (M)

M0 No clinical or radiographic evidence of distant metastases

cM0(i+)

No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumour cells in circulating blood, bone marrow, or other non-regional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases

M1Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm

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ANATOMIC STAGE/PROGNOSTIC GROUPS

Stage 0 Tis N0 M0

Stage IA T1* N0 M0

Stage IB T0 N1mi M0

T1 * N1mi M0

Stage IIA T0 N1** M0

T1 * N1 ** M0

T2 N0 M0

Stage IIB T2 N1 M0

T3 N0 M0

Stage IIIA T0 N2 M0

T1 * N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

Stage IIIB T4 N0 M0

T4 N1 M0

T4 N2 M0

Stage IIIC Any T N3 M0

Stage IV Any T Any N M1

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APPENDIX 4

MINIMUM DATASET FOR THE HISTOPATHOLOGY REPORTING OF BREAST CANCER

Patient Name:..........................................................................................................

Registration Number:................................Laboratory Number: ...............................

Complete histopathological diagnosis: .........................................................................

Specimen: .................................................................................................................

* Tumour Location: .....................................................................................................

* Size: Invasive cancer: ...............................................................................................

* Tumour type: ............................................................................................................

* Histological Grade: ................................................................................................... Tubule formation (score): .............................................................................................

Nuclear grade (score): .................................................................................................

Mitoses (score): ..........................................................................................................

* DCIS in Specimen: Present / Absent

DCIS grade: ................................................................................................................

Percentage of DCIS in tumour: .....................................................................................

DCIS in adjacent breast tissue: ....................................................................................

* Resection margins involved: YES (DCIS/ Invasive) NO

Orientation of involved margin: .....................................................................................

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Distance of margin from tumour (mm): .........................................................................

* Calcification: Present Absent

* Lymphovascular invasion: .........................................................................................

* Non-neoplastic breast : ............................................................................................

* Hormone receptor status

*Estrogen receptors: Positive / Negative

Percentage of nuclei stained: .......................................................................

Intensity of staining : .........................................................................

* Progesterone receptors: positive negative

Percentage of nuclei stained: ........................................................................

Intensity of staining: .....................................................................................

* HER-2 assessment: ..................................................................................................

Others: Please specify: ................................................................................................

..................................................................................................................................

* Axillary lymph node metastasis: Present Absent

Number of nodes involved / nodes examined: .................... / .......................

Extracapsular lymph node involvement: ........................................................

Micrometastasis: .........................................................................................

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LIST OF ABBREVIATIONS

ACS American cancer societyALND Axillary lymph node dissection

ASR Age-standardized incidence rateAUC Area under the curveAUS Axillary ultrasonography BCEI Breast cancer educational intervention BCN Breast care nurse BCS Breast conserving surgery

BDI-SF Beck depression inventory short form BI-RADS Breast imaging-reporting and data system

BPM Bilateral prophylactic mastectomy BPSO Bilateral prophylactic salpingo-oophorectomy BRCA Breast cancer gene mutation

BRCA1 Breast cancer gene 1BRCA2 Breast cancer gene 2

BSE Breast self examinationCB Core biopsy

CBE Clinical breast examinationCBT Cognitive behaviour therapy

CI Confidence intervalCISH Chromogenic in-situ hybridisationCMF Cyclophosphamide, methotrexate and fluorouracil CNB Core needle biopsy CPM Contralateral prophylactic mastectomy

CT Computerised tomographyDCIS Ductal carcinoma in situDFS Disease free survival

EBCTCG Early breast cancer trialists collaborative group ER/PR Estrogen-receptor/progesterone receptor

FDG-PET Fluorodeoxyglucose-positron emission tomography FEC 5-fluorouracil, epirubicin, and cyclophosphamide

FISH Fluorescent in-situ hybridisation FNAC Fine needle aspiration cytology H&E Standard haematoxylin and eosin

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HADS Hospital anxiety and depression scale

HER-2 Human epidermal growth factor receptor 2

HERA Herceptin Adjuvant

IDC Invasive ductal carcinoma

IHC Immunohistochemistry

ILC Invasive lobular carcinoma

INS Individual nurse support

IPS Individual psychosocial support

LABC Locally advanced breast cancer

LAR Lifetime attributable risk

LCIS Lobular carcinoma in situ

LHRH Luteinising-hormone-releasing hormone

LAR Lifetime attributable risk

MDD Major depressive disorders

MMG Mammography

MRI Magnetic resonance imaging

OS Overall survival

PCHCT Palliative and hospice care team

pCR Polymerase chain reaction

PET/CT Positron emission tomography/computerised tomography

PPV Positive predictive value

QoL Quality of life

RCT Randomised control trial

RR Relative risk

RRSO Risk reducing salpingo-oopherectomy

SBE Self breast examination

SCID Structured clinical interview for DSM disorders

SEGT Supportive expressive therapy

SISH Silver-enhanced in-situ hybridisation

SLNB Sentinel lymph node biopsy

SR Systematic review

TRAM Transverse rectus abdominis myocutaneous

USPTF US Preventive Task Force

WHEL Women’s healthy eating and living

WHR Waist hip ratio

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ACKNOWLEDGEMENT

The members of development group of these guidelines would like to express their gratitude and appreciation to the following for their contributions:

• Panel of external reviewers who reviewed the draft• Dr. Mohd Aminuddin Mohd Yusof, Head, CPG Unit for the valuable input and

feedback• Ms. Loong Ah Moi (Nursing Sister) who help in literature searching• Technical Advisory Committee for CPG for their valuable input and feedback• All those who have contributed directly or indirectly to the development of the

CPG

DISCLOSURE STATEMENT

The panel members had completed disclosure forms. None held shares in pharmaceutical firms or acts as consultants to such firms. (Details are available upon request from the CPG Secretariat)

SOURCES OF FUNDING

The development of the CPG on Management of Breast Cancer (2nd Edition) was supported financially in its entirety by the Ministry of Health Malaysia and was developed without any involvement of the pharmaceutical industry.

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Management of Breast Cancer 2nd Edition

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